Role of Gastrointestinal Hormones in the Proliferation of Normal and ...

0163-769X/03/$20.00/0 Endocrine Reviews 24(5):571–599Printed in U.S.A.Copyright © 2003 by The Endocrine Societydoi: 10.1210/er.2002-0028Role of Gastrointestinal Hormones in the Proliferation ofNormal and Neoplastic TissuesROBERT P. THOMAS, MARK R. HELLMICH, COURTNEY M. TOWNSEND, JR., AND B. MARK EVERSDepartment of Surgery, The University of Texas Medical Branch, Galveston, Texas 77555Gastrointestinal (GI) hormones are chemical messengers thatregulate the physiological functions of the intestine and pancreas,including secretion, motility, absorption, and digestion.In addition to these well-defined physiological effects, GI hormonescan stimulate proliferation of the nonneoplastic intestinalmucosa and pancreas. Furthermore, in an analogousfashion to breast and prostate cancer, certain GI cancers possessreceptors for GI hormones; growth can be altered byadministration of these hormones or by blocking their respectivereceptors. The GI hormones that affect proliferation, eitherstimulatory or inhibitory, include gastrin, cholecystokinin,gastrin-releasing peptide, neurotensin, peptide YY,glucagon-like peptide-2, and somatostatin. The effects of thesepeptides on normal and neoplastic GI tissues will be described.Also, future perspectives and potential therapeuticimplications will be discussed. (Endocrine Reviews 24:571–599, 2003)I. IntroductionII. GI HormonesA. GI hormone distribution, synthesis, and secretionB. GI hormone receptors and signal transduction pathwaysIII. Proliferation and Repair of Nonneoplastic Tissues by GIHormonesA. GastrinB. CCKC. BBS/GRPD. NTE. PYYF. GLP-2G. SomatostatinIV. Proliferation of Neoplastic Tissues by GI HormonesA. Gastric cancerB. Pancreatic cancerC. Colorectal cancerD. Other cancersV. Future Perspectives and Therapeutic ImplicationsA. Nonneoplastic GI diseasesB. GI cancersAbbreviations: AP, Activator protein; BBS, bombesin; BLP, BBS-likepeptide; BOP, N-nitrosobis (2-oxypropyl) amine; BrdU, bromodeoxyuridine;CCK, cholecystokinin; cGMP, cyclic GMP; CYS, cysteamine; ED,elemental diet(s); EGF, epidermal growth factor; G17-DT, gastrin-17-diphtheria toxoid; G-34, G34-NH 2 ; G-gly, G-17-gly; GI, gastrointestinal;GLP, glucagon-like peptide; Gly-G, glycine-extended G-17 peptide;GPCR, G protein-coupled receptor; GRP, gastrin-releasing peptide; IP,intervening peptide; JNK, Jun N-terminal kinase; MNNG, N-methyl-Nnitro-N-nitroguanidine;mTOR, mammalian target of rapamycin; MTX,methotrexate; NPY, neuropeptide Y; NT, neurotensin; NTR, NT receptor;PGDP, proglucagon-derived peptide; PI3K, phosphatidylinositol3-kinase; PP, pancreatic polypeptide; PT, gastrinoma; PYY, peptide YY;SAPK, stress-activated protein kinase; SCLC, small cell lung cancer;TPN, total parenteral nutrition; TVF, Thiry-Vella fistula.I. IntroductionGASTROINTESTINAL (GI) HORMONES are chemicalmessengers that regulate intestinal and pancreaticfunction, including regulation of secretion, motility, absorption,digestion, and cell proliferation. These hormones aresecreted by endocrine cells, which are widely distributedthroughout the GI mucosa and pancreas. Although thesehormones were initially described as solely endocrine products,subsequent studies have shown that they can act in anautocrine or paracrine fashion to affect cellular function. GIhormones may also serve as transmitting agents for nervousimpulses discharged into blood vessels after nervous stimulationin a true neurocrine fashion. This review will focuson the trophic effects of GI hormones on nonneoplastic andneoplastic tissues.II. GI HormonesThe trophic GI hormones that have been best characterizedand will be discussed in this review include gastrin, cholecystokinin(CCK), bombesin (BBS)/gastrin-releasing peptide(GRP), neurotensin (NT), peptide YY (PYY), glucagon-likepeptide (GLP)-2, and somatostatin. These hormones sharemany of the same attributes, such as the presence of largeprecursor molecules, multiple active isoforms, multiplemembrane-bound receptors, and signaling through multipleintracellular pathways. The distribution, synthesis, and secretionof these hormones as well as the receptors and signalingpathways that mediate the hormone response will bebriefly described.A. GI hormone distribution, synthesis, and secretion1. Gastrin. The presence of gastrin was postulated in 1906 byEdkins (1), but it was not until 1938 that Komarov (2) prepareduseful, histamine-free antral extracts of this gastricstimulant. Gastrin is now firmly established as the physiologicalregulator of gastric acid secretion and an importantregulator of gastric mucosal cell proliferation (3). The majorsite of gastrin synthesis and secretion is the gastrin-containingcell (G cell) in the antropyloric mucosa (4–6). Otherminor sites of gastrin production include the endocrine cells571Downloaded from edrv.endojournals.org by on July 16, 2007

572 Endocrine Reviews, October 2003, 24(5):571–599 Thomas et al. • Gastrointestinal Hormones and Proliferationof the pancreas (7), pituitary (8), and extraantral G cells (9).Gastrin release is stimulated by food components, particularlyaromatic amino acids and amine derivatives of aminoacids, and is inhibited by luminal acid (10).Human progastrin, the precursor of gastrin, consists of a21-amino-acid signal peptide, a 37-amino-acid N-terminalextension, the gastrin-34 sequence, and a 9-amino-acid C-terminal extension (3, 10). In antral G cells, progastrin isstored and processed into secretory granules, and N-terminaland C-terminal extensions are removed by prohormone convertases.The C-terminal basic amino acids are sequentiallyremoved by a carboxypeptidase, which results in the formationof glycine-extended G34 (G34-gly). G34-gly is amidatedby peptidyl glycine -amidating monooxygenase toform G34-NH 2 (G-34) or cleaved at internal lysine/lysineresidues to form G-17-gly (referred to as G-gly) (10). Recentstudies have demonstrated that the majority of G-17-NH 2(also known as gastrin or G-17) arises from the conversion ofG34-NH 2 to G-17-NH 2 , rather than by amidation of G-gly,suggesting that the conversion of G-gly to amidated G-17 isblocked and that G-gly is a terminal, secondary end-productof progastrin processing in normal antral G cells (10, 11). Thisis contrasted by evidence in colon cancer cells that gastrinbypasses the processing machinery and is expressed inlarger, unprocessed forms that are transported in secretoryvesicles and continuously fused with the plasma membraneand released (11).2. CCK. CCK was described in 1928 by Ivy and Oldberg (12)as a contaminant in impure secretin preparations. These impuritieswere noted to produce gallbladder contraction indogs and cats. In 1943, Harper and Raper (13) identified asingle agent extracted from intestinal samples that possessedpancreatic-stimulating activity. After complete purificationand sequencing, it was determined that this single compound,CCK, was responsible for gallbladder contractionand pancreatic enzyme secretion (14). Other actions of CCKinclude inhibition of gastric emptying, stimulation of bowelmotility, potentiation of insulin secretion, and trophic effectson the pancreas and GI mucosa (3). CCK release is stimulatedby fats, proteins, and amino acids.CCK is produced by endocrine cells of the gut (primarilyduodenum and jejunum), the neurons of the brain, and theperipheral nervous system of the GI tract (15–18). Ultrastructuralstudies demonstrate that the cells are identical to I cellsof the human intestine (19). CCK neurons are found in themyenteric plexus, submucosal plexus, and circular musclelayers of the distal intestine and colon (9). PostganglionicCCK nerve fibers are found in the pancreas surrounding theislets of Langerhans (20). Furthermore, although CCK hasnot been found in the intrinsic neurons of the stomach andduodenum, CCK cells are in the celiac plexus and can befound in the vagus nerve, especially after injury (21, 22).The molecular forms of CCK are diverse and appear to betissue-specific (23, 24). The most abundant form in the brainappears to be CCK-8, although significant amounts of largercarboxy-amidated forms like CCK-33, CCK-58, and CCK-83have been isolated.3. BBS/GRP. BBS, a tetradecapeptide originally isolated fromthe skin of the frog Bombina bombina, is analogous to mammalianGRP (24). In general, BBS/GRP may be thought of asa universal on-switch with predominantly stimulatory effects.BBS/GRP stimulates the release of all GI hormones,intestinal and pancreatic secretion, and motility (24). Themost important functions of BBS/GRP are antral gastrinrelease and stimulation of gastric acid secretion (25, 26). Thispeptide also stimulates growth of the GI mucosa and pancreas(24).BBS/GRP-like immunoreactivity is widely distributedthroughout the GI tract of rats, guinea pigs, dogs, and humans(27–31), predominantly in the neuronal populations ofthe gut. GRP is most abundant in the stomach, with GRPpositivecells and fibers innervating the oxyntic and antralmucosa and circular muscle.4. NT. NT, a tridecapeptide originally isolated from bovinehypothalamus (32), is localized mainly in the central nervoussystem (predominantly hypothalamus and pituitary) and inendocrine cells (N cells) of the jejunal and ileal mucosa (33,34). NT is released in response to increased intraluminal fats(35, 36) and has numerous functions in the GI tract, includingstimulation of pancreatic secretion (37), inhibition of gastricand small bowel motility (38), facilitation of fatty acid translocationfrom the intestinal lumen (39), and growth stimulationof various GI tissues (34, 40–43).NT is produced from a single precursor, preproneurotensin,that contains both NT 1–13 and the related peptide,neuromedin N. Neuromedin N comprises the C-terminalportion of the proneurotensin peptide after NT is removed.NT 1–13, the major product of proneurotensin in the ileumand brain (44), is cleaved at or soon after secretion at thedibasic arg 8 -arg 9 residues, resulting in the inactive degradationproduct NT 1–8 and the biologically active NT 9–13.Substance P, muscarinic agonists (carbachol), catecholamines,and BBS/GRP stimulate NT release, suggesting that a complexinterplay of neural, endocrine, and luminal mechanisms is responsiblefor NT release and physiological functioning (45–47).5. PYY. PYY, a 36-amino-acid peptide, is homologous to twoother regulatory peptides, pancreatic polypeptide (PP) andneuropeptide Y (NPY) (3). Both the rat and human PYY geneshave been isolated and characterized (48, 49). The conservedstructural organization of the genes encoding PYY, NPY, andPP suggests that each gene is derived from duplication of acommon ancestral gene. The biological actions of PYY includeinhibition of pancreatic bicarbonate secretion and contractionof the gallbladder (50). In addition, PYY inhibitsgastric emptying and intestinal transit and has been postulatedas an agent that contributes to the ileal brake phenomenon,a negative-feedback mechanism that promotes intestinalabsorption (3). PYY can also stimulate growth of the GImucosa (51).PYY, NPY, and PP are synthesized as prepropeptides consistingof a signal peptide followed by the 36-residue activepeptide, a cleavage-sequence Gly-Lys-Arg, and a carboxyterminalflanking peptide (52, 53). During processing, theprecursor is cleaved at the carboxy terminal by a specificprohormone convertase. The Lys-Arg sequences are thenlysed by a carboxypeptidase, and the carboxy-terminal tyrosineis amidated. Typical enteroendocrine cells, with longDownloaded from edrv.endojournals.org by on July 16, 2007

Thomas et al. • Gastrointestinal Hormones and Proliferation Endocrine Reviews, October 2003, 24(5):571–599 573basal processes, are visualized by immunohistochemistry inthe mucosa of the ileum, colon, and rectum (54).6. GLP. GLPs are a group of peptides known as the enteroglucagons.The enteroglucagons are products of the samegene that produces glucagon in the pancreatic -cell (3). Theintestinal L cell produces two elongated glucagons, glicentinand oxyntomodulin, and both of the enteroglucagons, GLP-1and GLP-2 (55). Both GLP-1 and GLP-2 have effects on nutrientabsorption and GI tract physiology; however, thesetwo peptides have distinct roles. GLP-1 has a significanteffect on blood glucose levels, lowering blood glucose levelsvia stimulation of insulin secretion (55), thus suggesting thatGLP-1 may provide some therapeutic benefit to patients withdiabetes. GLP-2 displays minimal effects on glucose levels,but demonstrates potent trophic effects on intestinal epithelia(55).Both GLP-1 and GLP-2 are released when the L cell isexposed luminally to the products of a mixed meal (carbohydrateor fat) (55). L cells are most abundant in the mucosaof the ileum and colon; they are the second most numerouspopulation of endocrine cells in the human intestine, afterenterochromaffin cells (56). Both GLP-1 and GLP-2 are rapidlycleaved by the exopeptidase dipeptidyl peptidase IV(55). Current concepts of L cell regulation involve integrationof hormonal messages from peptides, such as GRP and glucose-dependentinsulinotropic polypeptide, and neuronalcontrol (55).7. Somatostatin. Somatostatin was isolated and characterizedfrom ovine hypothalamic tissue during a search for a GHreleasingfactor (57). Since the identification and purificationof somatostation-14, precursor forms of greater molecularweight, including somatostatin-28, with somatostatin-14making up the C terminus, and larger precursor forms of 120or more amino acids have been identified (58). All of thesepeptides exert biological activity but differ in their relativepotency.Somatostatin has been detected in the nerves and cellbodies of the central and peripheral nervous systems, includingthe autonomic nervous system of the GI tract and theendocrine-like D cells of the pancreatic islets and mucosa ofthe stomach and intestine (3). More than 90% of the somatostatinimmunoreactivity in the human gut is located withinthe mucosal endocrine D cells (58). In addition, somatostatinis located in the nerves of the myenteric plexus. Somatostatinin the pancreas is located in the D cells at the periphery of theislets closely associated with the -cells (59).Somatostatin is a regulatory-inhibitory peptide, which, incontrast to BBS/GRP, may be considered as the universalendocrine off-switch. Somatostatin inhibits the release of GHand somatomedin C and all known GI hormones (3). Somatostatinalso inhibits gastric acid secretion and motility, intestinalabsorption, and pancreatic bicarbonate and enzymesecretion, and selectively decreases splanchnic and portalblood flow (60). In addition, somatostatin can inhibit thegrowth of normal and neoplastic tissues (61–67).B. GI hormone receptors and signal transduction pathways1. Receptors. GI hormone-stimulated signal transduction occurswith the binding of hormones to their cognate cell surfacereceptor, the G protein-coupled receptor (GPCR) (68).The GI hormone-GPCRs have the typical structural featuresof G protein binding seven-transmembrane receptors (Fig. 1).The receptors for gastrin, CCK, BBS/GRP, NT, PYY, GLP-2,and somatostatin, which are respectively, the gastrin/CCK-Breceptor, CCK-A receptor, GRP receptor, the NT receptor(NTR), NPY receptor, GLP-2 receptor, and the somatostatinreceptor (five subtypes), are all GPCRs (3, 55). GPCRs regulatea number of physiological processes, including proliferation,growth, and development (68). It was originallythought that, in order for GPCR signaling to occur, specificinteractions between the GI hormone and the receptor werenecessary to produce conformational changes in the receptorand stimulate intracellular signal transduction networks.However, recent studies suggest a more complex regulationof the GPCRs through: 1) dimerization with themselves andother receptors; 2) activation of differing G proteins; 3) internalizationand desensitization; and 4) ability to change inconformation and interactions with empty, or inactive, receptors(69). It is suggested that this complicated mechanismof regulation allows peptides to interact with GPCRs to stimulatediverse intracellular signaling pathways and ultimatelyaffect multiple physiological functions, depending on celltype.2. Signal transduction pathways. The seven transmembranespanning-helical domains function as ligand-regulatedguanine nucleotide exchange factors for the intracellular heterotrimericG proteins (68). Heterotrimeric G proteins arecomposed of the products of three gene families encoding -,-, and -subunits (68). The agonist-activated GPCR catalyzesthe exchange of GTP for GDP bound to the G-subunit,as well as the dissociation of the GTP-G from its cognateG dimer (Fig. 2A) (68). The activated GTP-G- and Gsubunits,in turn, regulate the activity of various intracellulareffector proteins such as phospholipases, adenylyl cyclases,protein kinases, membrane ion channels, and members of theRas family of GTP-binding proteins (68). In addition, basedon structural similarities, the 20 identified G-subunits havebeen divided into four subfamilies and assigned an effectorpathway based on current evidence. The four are: 1) thecholera toxin-sensitive () subunits that stimulate adenylcyclase and increase cAMP levels; 2) the pertussis toxinsensitive( i/o ) subunits that inhibit adenylyl cyclase activity;3) the pertussis toxin-insensitive ( q/11/14 ) subunits that stimulatemembrane phospholipases; and 4) the 12/13 subfamilythat links GPCR to the Ras-related GTP-binding protein, Rho(68). Additionally, 12 G- and 6-G subunits have been identified;these -dimers have been linked to the signalingmolecules phosphatidylinositol 3-kinase (PI3K) and selectforms of adenylyl cyclase and receptor kinases (68).Among the multiple intracellular signaling pathways thatmediate the proliferative effects of GPCRs, a family of relatedserine-threonine kinases, collectively known as ERKs orMAPKs, appear to play a central role (70). After phosphorylationby their immediate upstream MAPK kinase, membersof the MAPK family translocate to the nucleus, wherethey phosphorylate transcription factors, thus regulating theexpression of genes that control growth (71). Hormones actas ligands to eventually activate p42 and p44 MAPK (Fig. 2B)Downloaded from edrv.endojournals.org by on July 16, 2007

574 Endocrine Reviews, October 2003, 24(5):571–599 Thomas et al. • Gastrointestinal Hormones and ProliferationFIG. 1. GPCR: amino acid sequence for the structure of typical GPCR including the seven-transmembrane domains. Amino acid sequencesof CCK-B (A) and CCK-A (B) receptors indicating similar seven-transmembrane structure and about 50% amino acid identity. Identical aminoacids are shaded. The NH 2 portion is extracellular, and the COOH portion is intracellular. [From J. H. Walsh: Physiology of the GastrointestinalTract, Vol 1, pp 1–128, 1994 (3). © Lippincott Williams & Wilkens.](72). The mechanism by which this occurs involves a complexinterplay of several known nonreceptor kinases and receptorkinases. The ability of tyrosine kinase inhibitors to reduce theactivation of MAPK by GPCR (73) and the rapid tyrosinephosphorylation of Shc (Src homology and collagen) afterGPCR stimulation with the consequent formation of Shc-Downloaded from edrv.endojournals.org by on July 16, 2007

Thomas et al. • Gastrointestinal Hormones and Proliferation Endocrine Reviews, October 2003, 24(5):571–599 575FIG. 2. Diversity of GPCRs. A, Hormones use GPCRs to stimulate cytoplasmic and nuclear targets through heterotrimeric G protein-dependentand -independent pathways. B, Multiple pathways link GPCRs to MAPK. Activated MAPK translocates to the nucleus and phosphorylatesnuclear proteins, including transcription factors, thereby regulating gene expression. C, Novel signaling pathways that connect GPCRs to JNK,p38 isoforms, and big mitogen-activated kinase 1 (ERK5): molecules that link GPCRs to the different members of the MAPK family. EPAC,Exchange protein activated by cAMP; FAK, focal adhesion kinase; GAP, GTPase-activating protein; GEF, guanine nucleotide exchange factor;GRF, guanine-nucleotide releasing factor; MEK and MKK, MAPK kinase; MEKK, MAPK kinase kinase; MLK, mixed lineage kinase; PKA,protein kinase A; PLC, phospholipase C; PYK2, proline-rich tyrosine kinase 2; RGS, regulator of G protein signaling; RTK, receptor tyrosinekinase. [Adapted with permission from M. J. Marinissen and J. S. Gutkind: Trends Pharmacol Sci 22:368–376, 2001 (68). ©Elsevier Science.]Downloaded from edrv.endojournals.org by on July 16, 2007

576 Endocrine Reviews, October 2003, 24(5):571–599 Thomas et al. • Gastrointestinal Hormones and ProliferationGrb2 (growth factor receptor-bound 2) complexes (74) provideevidence that tyrosine kinases link GPCRs to the Ras-MAPK pathway.Additionally, GPCRs link to the Jun N-terminal kinase(JNK), p38 MAPK, and the big mitogen-activated kinase 1 orERK5 pathways (Fig. 2C) (68). JNK, also termed stress-activatedprotein kinase (SAPK), is structurally related toMAPK, but the pathways used by GPCRs to activate thesekinases are different. Activated Rac and Cdc42 affect JNKactivation through stimulation from free -dimers and G 12and G 13 .Four p38 MAPKs have been described, p38 (CSBP-1), p38, p38 (ERK6 or SAPK3), and p38 (SAPK4) (75). Yamauchiet al. (76) demonstrated that G q and dimers activatep38. Two nonreceptor tyrosine kinases, Btk and Src (77, 78),have been associated with this process. ERK5 can be activatedby oxidative stress and plays a role in early geneexpression (79). GPCRs can potently stimulate ERK5 througha mechanism that involves G q and G 13 , independent ofRho, Rac1, and Cdc42 (80, 81). Furthermore, ERK5 regulatesearly gene expression through the phosphorylation of thetranscription factor, myocyte enhancer factor 2 (80).The molecular mechanisms through which GPCRs transducesignals are complex and likely involve multiple signalpathways. In addition, the signaling pathways are likelycell-specific, which may explain the diverse physiologicalfunctions controlled by GI hormones ranging from regulationof secretion, mobility, and, in some instances, growthdepending upon the target tissue.III. Proliferation and Repair of NonneoplasticTissues by GI HormonesGI hormones can alter proliferation of the normal gut andpancreas. In this section, we will review the effects of thestimulatory hormones gastrin, CCK, BBS/GRP, NT, PYY,and GLP-2 and the inhibitory hormone, somatostatin, on thegrowth of the pancreas and mucosa of the GI tract.A. GastrinGastrin is the GI hormone that has been best characterizedfor its trophic effects. In addition to stimulating acid secretionfrom gastric parietal cells, gastrin is the single most importanttrophic hormone of the stomach (82).1. Stomach. The trophic effect of gastrin was initially describedmore than 30 yr ago in two separate reports. Johnsonet al. (83) and Crean et al. (84) demonstrated that pentagastrin,a synthetic gastrin analog containing the active carboxylterminaltetrapeptide, increased protein synthesis and parietalcell mass in rats. These results were further confirmedusing the natural amidated gastrins, G-17 and G-34. G-17 andG-34 produced maximal stimulation of DNA synthesis in theoxyntic mucosa, duodenum, and colon at doses of 13.5 and6.75 nmol/kg, respectively.In the stomach, the oxyntic, acid-secreting mucosa andenterochromaffin-like cells (cells that produce histaminescritical to parietal cell acid production) are particularly sensitiveto the trophic actions of gastrin (85). The removal ofendogenous gastrin, by antral resection, results in mucosalatrophy that can be prevented by administering exogenousgastrin.Overexpression of either unprocessed gastrins or the amidatedgastrins (G-17 and G-34) in transgenic mice results ina 2-fold elevation in serum-amidated gastrin and producesmarked thickening of the oxyntic mucosa with increasedbromodeoxyuridine (BrdU) labeling, representing an 85%increase in cells undergoing proliferation (86, 87). These findingsare further supported by results in athymic nude micebearing xenografts of a transplanted human gastrinoma (PT)demonstrating gastric and duodenal mucosal hyperplasia(Fig. 3) (Ref. 88).In gastrin-deficient mice (89, 90), a 35% decrease in parietalcell mass with no decrease in basal fundic proliferation ratesis noted, compared with wild-type control mice, suggestingthat, although gastrin can stimulate proliferation, it is notnecessarily required for basal proliferation. Taken together,these experimental results, using different in vivo models,indicate that amidated gastrin can stimulate proliferation ofthe oxyntic mucosa, resulting in increased parietal and enterochromaffin-likecell production.2. Small intestine. The role of gastrin as a stimulant for smallbowel mucosal growth is less clear. Johnson et al. (83) showedthat [ 3 H]thymidine incorporation and DNA synthesis of ratduodenal tissues were significantly increased by pentagas-FIG. 3. Human PT xenografts produce gastrin, resultingin gastric and duodenal mucosal growth. A, Stomachsopened along greater curvature from mice with PTtumors (top) and controls (bottom). B, Effects of PT onthe mouse gastric fundus (n 5 PT mice; n 10 controlmice; *, P 0.05). [Adapted with permission from J. R.Upp Jr. et al.: Surgery 104:1037–1045, 1988 (88). ©Mosby, Inc.]Downloaded from edrv.endojournals.org by on July 16, 2007

Thomas et al. • Gastrointestinal Hormones and Proliferation Endocrine Reviews, October 2003, 24(5):571–599 577trin, G-17, and G-34 administration. Schwartz and Storozuk(91) found that exogenous gastrin (13.5 nmol/kgd) enhancedgrowth of jejunoileal segments obtained from 19- to20-d gestation fetal rats transplanted sc in adult rats. Inaddition, administration of gastrin enhanced the absorptionof galactose and glycine, suggesting that gastrin increasesfunctional activity as well as growth. Subsequent studies,however, using both pentagastrin and natural G-17 havefailed to demonstrate significant trophic effects of gastrin inthe small bowel (jejunum and ileum) mucosa of the adult ratas measured by vincristine-arrested metaphase (92). An explanationfor these differing results is not entirely clear butmay pertain to different experimental measures of proliferation.Therefore, although the trophic effects in the oxynticand duodenal mucosa are well established, the trophic effectof gastrin in the remaining small intestine is currently consideredminimal, at best.3. Colon. Similar to the small bowel, evidence for a trophiceffect of gastrin in the colon is limited. In earlier studies byJohnson (93), administration of natural porcine gastrins stimulatedDNA synthesis in the colon. In contrast, hypergastremia,induced through acid blockade by either omeprazoleadministration (94) or fundectomy (95), failed to produceproliferation of either normal colon or the colon carcinomacells transplanted from an original 1,2-dimethylhydrazineinducedadenocarcinoma.As opposed to results using amidated gastrin, recent experimentsusing G-gly demonstrate colonic proliferation,sparking renewed interest in a role for gastrin precursorproducts in colonic growth. Koh et al. (96) generated micethat overexpress progastrin truncated at glycine-72 (MTI/G-GLY), which demonstrates elevated serum and mucosallevels of G-gly compared with wild-type mice. MTI/G-GLYmice display a 43% increase in colonic mucosal thickness anda 41% increase in the percentage of goblet cells per crypt.Furthermore, administration of G-gly to gastrin-deficientmice resulted in a 10% increase in colonic mucosal thicknessand an 81% increase in colonic proliferation (as measured byBrdU) when compared with control mice. Thus, these data,using exogenous administration and genetic mouse models,demonstrate that G-gly is a potent stimulator of colonicproliferation.4. Pancreas. The role of gastrin in normal pancreatic growthis also believed to be stimulatory. In two separate studies,investigators in our laboratory have demonstrated small,albeit significant, increases in pancreatic growth. In the firststudy, young adult rats were given pentagastrin, NT, or BBSin combination with an elemental diet (ED) (33). Pentagastrinat a maximal dose, 250 g/kg, increased pancreatic weightcompared with control rats. In the second study, pentagastrin(100 g/kg) was given to young (3-month-old), adult(12-month-old), and aged (24-month-old) rats (97). In youngrats, pentagastrin increased pancreatic weight, DNA, RNA,and protein content. In adult rats, however, pentagastrinonly produced increases in RNA content, whereas aged ratsshowed no trophic effect. These results suggest that the effectsof gastrin on pancreatic growth are dependent uponage. Further support for a stimulatory effect of gastrin onpancreatic cells is provided by in vitro studies using the ratpancreatic acinar cancer cell line, AR42J, demonstrating thatgastrins can induce cellular proliferation through stimulationof the c-fos transcription factor via protein kinase C-dependent and independent mechanisms (98).In contrast, Chen et al. (99) induced hypergastrinemia inmale Sprague-Dawley rats by continuous infusion of humanLeu 15-gastrin-17, by fundectomy, or by treatment with omeprazole.Gastrin infusion or omeprazole treatment did notaffect pancreatic weight and DNA content, whereas fundectomyincreased pancreatic weight and DNA content. Thesefindings suggest that endogenous gastrin level variations donot directly play a role in pancreatic growth. Further studiesare needed to conclusively establish the differences ingastrin-related hormonal signaling affecting the growth ofthe pancreas.B. CCKCCK, acting through CCK-A receptors, is one of the mostpotent secretagogues regulating pancreatic acinar cells (100).Additionally, CCK stimulates the growth of the pancreas inexperimental studies (101, 102). However, evidence for CCKplaying a major role in the growth of the GI mucosa (stomach,small bowel, and colon) is limited.1. GI mucosa. Administration of CCK and secretin preventedatrophy in the jejunum and ileum of dogs given total parenteralnutrition (TPN) as a sole nutrient source (103). Inaddition, administration of these peptides increased galactoseabsorption, suggesting that CCK is a positive enterotrophicfactor for the gut. Weser et al. (104) provided additionalevidence that CCK alone, or in combination withsecretin, could prevent TPN-associated jejunal and ileal atrophyin rats. In subsequent studies, Fine et al. (105), usingintestinal bypass models, demonstrated that the trophic responsenoted by CCK and secretin in the small bowel was theindirect result of increased pancreatobiliary secretion, as opposedto a direct stimulatory effect of these peptides on thegut mucosa. Confirmation of the lack of a direct effect of CCKon small bowel growth was provided by Stange et al. (106)using cultured rabbit jejunum and ileum preparations.2. Pancreas. In contrast, the trophic effects of CCK on thepancreas have been demonstrated by a number of experimentalmodels (107–113). In one study, the effects of camostate(400 mg/kg), a potent inhibitor of trypsin (which blocksserine proteases), were compared with the effects of chronicexogenous administration of CCK-8 with or without administrationof the CCK-receptor antagonist, CR 1409 (114).Chronic (10-d) camostate feeding increased pancreaticweight, protein, and DNA content, which was associatedwith increased CCK plasma levels. The administration ofexogenous CCK produced similar increases in pancreaticgrowth. The combination of camostate and CCK-8 producedan additive stimulatory effect on the pancreas. The CCKreceptorantagonist, CR 1409, completely abolished the trophiceffects of exogenous CCK-8 and inhibited the effects ofchronic camostate feeding. Furthermore, CR 1409 alone decreasedpancreatic weight, DNA, and protein content of rats.Additionally, other studies have substantiated and con-Downloaded from edrv.endojournals.org by on July 16, 2007

578 Endocrine Reviews, October 2003, 24(5):571–599 Thomas et al. • Gastrointestinal Hormones and Proliferationfirmed a stimulatory effect of CCK on the pancreas (110–113).Taken together, these studies provide clear evidence thatCCK is a potent stimulant for pancreatic growth.Recently, the cellular mechanisms regulating the proliferativeeffect of CCK have been examined. Similar to gastrin,CCK activates the MAPK cascade, leading to the activationof ERK, JNK, and p38 MAPK in the pancreas (115). In addition,there is evidence that other signaling pathways, suchas the PI3K-mTOR (mammalian target of rapamycin)-p70 s6kpathway, are involved in CCK-stimulated mitogenesis andcellular proliferation (115). p70 s6k is physiologically importantfor phosphorylating the small ribosomal subunit proteinS6, which was the first regulated phosphoprotein identifiedin pancreatic acinar cells (115), thereby facilitating the synthesisof RNA. Bragado et al. (116) demonstrated the phosphorylationand activation of p70 s6k in rat pancreatic acini byCCK, carbachol, and BBS, but not by cAMP, phorbol ester, orcalcium ionophore. This activation was blocked by rapamycin,which inhibits mTOR, and by wortmannin (a PI3K inhibitor).In addition, the PI3K-mTOR pathway is known toplay a role in activating protein synthesis by phosphorylatingthe binding protein eIF4E, the translation initiation factorthat binds to the 7-methyl guanosine cap at the 5 end of mosteukaryotic mRNA molecules (117). This binding protein,known as eIF4E-BP or PHAS-I, possesses multiple phosphorylatedsites and, when sufficiently phosphorylated, dissociatesfrom eIF4E, which can then interact with eIF4G (a scaffoldprotein) together with eIF4A (a RNA helicase) to forma complex, known as eIF4F, and stimulate protein synthesis.CCK stimulation of rat pancreatic acini leads to PHAS-Iphosphorylation and initiation of a complex formation (118).C. BBS/GRPBBS/GRP stimulates pancreatic, gastric, and intestinal secretion,and gut motility, smooth muscle contraction, andrelease of all gut hormones (29). In addition, BBS/GRP is apotent trophic factor for the GI tract and pancreas.1. Stomach. Lehy and colleagues (119, 120) reported that BBS,given orally or sc, stimulated the growth of gut mucosa andpancreas in neonatal rats. In this study, 7-d-old rats wereinjected sc with BBS (20 g/kg) twice daily for 6 d. Gastricweight, fundic and antral mucosal height, and the density ofparietal cells were increased in BBS-treated pups comparedwith saline-treated controls.Dembinski et al. (121, 122) demonstrated that BBS, administeredto rats for 7 successive days, significantly increasedthe weight and RNA and DNA contents of the oxyntic mucosaof the stomach and the duodenal mucosa; somatostatinattenuated the proliferative effect of BBS. Antrectomy, whichremoves the gastrin-secreting cells, and the CCK receptorinhibitor, L-364,718, partly reduced but did not abolish theproliferative effects of BSS, suggesting that the growthenhancingmechanisms of BBS involved gastrin and CCKstimulation. More importantly, these studies confirmed thatBBS had direct effects on the gastroduodenal mucosa.Later, Dembinski et al. (122) extended their initial findingsby assessing the effects of the BBS/GRP receptor antagonist,RC-3095, on BBS-mediated growth. BBS (10 g/kg) administeredthree times daily for 2dinfasted rats significantlyincreased the rate of DNA synthesis in the gastroduodenalmucosa and pancreas as measured by the incorporation of[ 3 H]thymidine; this proliferative effect was abolished by RC-3095. These results provide further evidence that BBS/GRPstimulates the growth of the stomach and duodenum andthat these effects are due predominantly to a direct effect ofBBS/GRP stimulation.2. Small intestine. BBS also stimulates growth of the remainderof the small bowel mucosa. We examined the effects of BBSin the prevention of gut mucosal atrophy in Sprague-Dawleyrats given liquid ED (33). Four groups of rats were given anED and injected with saline (control), pentagastrin (250 g/kg), NT (300 g/kg), or BBS (10 g/kg) sc every 8 h. A fifthgroup was fed a regular chow diet. Atrophy of the ilealmucosa was apparent on d 6 and 11, and atrophy of thejejunal mucosa was present by d 11. BBS prevented jejunalmucosal atrophy and significantly increased ileal mucosalgrowth (mucosal weight, RNA, DNA, protein content) comparedwith control.Chu et al. (123) determined whether the trophic actions ofBBS on the small bowel were mediated by nonluminal orluminal (i.e., pancreaticobiliary secretion) factors by constructionof isolated small bowel loops [i.e., Thiry-Vella fistulas(TVFs)]. BBS increased mucosal weight, DNA, and proteincontent in both jejunal and ileal TVF compared withcontrol animals, suggesting that BBS-mediated stimulationof small bowel mucosal growth is mediated by factors thatare independent of luminal contents and pancreaticobiliarysecretion.In addition to its effects on gut mucosal growth, BBS exhibitsprotective effects in the gut after injury. Using a lethalenterocolitis model in rats induced by the chemotherapeuticagent methotrexate (MTX), BBS enhanced gut mucosalgrowth and significantly inhibited mortality in rats (124). Thebeneficial effect of BBS on survival was noted when BBS wasgiven before or at the same time as MTX, which suggestedthat BBS may act through additional mechanisms other thangut mucosal growth alone. One possibility is that BBS mayproduce its beneficial effects through enhancement of theimmune system, which is a known action of BBS (125).3. Colon. Studies assessing the effects of BBS/GRP on thecolonic mucosa are limited but, similar to the small bowel,appear to support a trophic effect of this agent in the colon.Johnson and Guthrie (126) demonstrated that BBS (20 g/kg,three times daily for 7 d) stimulated colonic mucosal growth.Puccio and Lehy (119) found that administration of BBSorally in the neonatal period stimulated colonic growth. Incontrast, we have not detected a proliferative effect of BBS inthe colon of chow-fed rats after 7 or 14 d (127). In rats givenan ED, BBS produced a proliferative effect only in the proximalcolon. Therefore, although BBS appears to exert a trophiceffect on the colonic mucosa, the effects are less pronouncedthan in the stomach or small bowel.4. Pancreas. A number of studies have shown that BBS stimulatesthe growth of the pancreas (97, 119, 120, 128). Forexample, Lehy and colleagues (119, 120) demonstrated atrophic response for BBS in the pancreas as well as other GIDownloaded from edrv.endojournals.org by on July 16, 2007

Thomas et al. • Gastrointestinal Hormones and Proliferation Endocrine Reviews, October 2003, 24(5):571–599 579tissues. In addition, electron morphometric analysis indicatedthat the increase in pancreatic weight was due to hypertrophyof the acinar cells. Increases in pancreatic chymotrypsinand trypsinogen content were noted, with little effecton lipase or colipase and amylase levels. Similar to its effectson the pancreatic acini, BBS stimulates endocrine cells of thepancreas (129).Liehr et al. (130) assessed the role of CCK in BBS-inducedgrowth in rats. Sprague-Dawley rats received sc injections ofBBS every 8 h for 5 d, alone or in combination with the CCKreceptor antagonist, L-364,718. BBS produced a dose-dependentincrease in pancreatic weight, DNA and protein content,as well as amylase and chymotrypsinogen levels. L-364,718significantly inhibited pancreatic growth induced by a highconcentration (5 nmol/kg) of BBS but had minimal effects ongrowth induced by lower dosages of BBS. These results suggestthat low doses of BBS stimulate pancreatic growth in adirect manner, independent of CCK, whereas high doses ofBBS act in part through CCK release.More recently, Fiorucci et al. (131) found that chronic BBSadministration stimulated pancreatic regeneration after pancreatectomyin pigs. Furthermore, these studies examinedthe cellular processes that may be regulated by BBS. Threegroups of pigs underwent sham operation, subtotal distalpancreatectomy, or subtotal pancreatectomy combined withBBS for 4 wk. After treatment, the pancreas was removed,weighed, and assayed for p42 and p44 MAPK, p46 Shc ,p52 Shc , p66 Shc , and Grb2. BBS administration resulted in a100% increase in residual pancreatic tissue when comparedwith control animals and approximately a 3-fold increase inthe rate of pancreatic acinar cell proliferation. Also, BBSadministration significantly increased p46 Shc /p52 Shc andMAPK expression and/or activity in whole pancreas extracts.These results further demonstrate a proliferative effectof BBS in a large animal model and provide evidence that BBScan stimulate cell proliferation via the MAPK pathway.Upp et al. (128) demonstrated that BBS had both direct andindirect actions in the pancreas. Polyamine synthesis, anessential part of DNA synthesis, was assessed with BBS administrationover a time course. BBS produced significantpancreatic hyperplasia (increased pancreatic weight, protein,and DNA content) after 14 d of treatment. CR1409, the CCKreceptor antagonist, inhibited only BBS-mediated increasesin DNA content. BBS stimulated polyamine biosynthesis asearly as 2 h after administration; CR1409 did not inhibit thisincrease in polyamines. These results suggested that the trophicactions of BBS are both direct and indirect and that thedirect effects are mediated by polyamine synthesis.D. NTThe physiological functions of NT in the GI tract includestimulation of pancreatic and biliary secretions (37) and inhibitionof small bowel and gastric motility (38). In addition,NT stimulates growth of the gastric antrum, small bowel (33,34, 42), colon (132), and pancreas (40, 133).1. Stomach. Feurle et al. (40) demonstrated that sc administrationof high dosages of NT for 2 wk increased proteinconcentration and thickness of the gastric antrum in Wistarrats, whereas DNA content and weight were not affected. Incontrast, Hoang et al. (134) noted that NT alone had no effecton the oxyntic gland area or the antrum, but it inhibitedincreases in antral weight, DNA, and protein induced bysecretin. The effects of NT on antral growth are, therefore,minimal at best and may occur with prolonged, high dosagesof NT.2. Small bowel. In contrast to the stomach, the trophic effectsof NT in the small bowel are more pronounced. Wood et al.(42) first noted that NT stimulated the small bowel mucosaof rats fed a normal chow diet. We have shown that administrationof NT prevents gut mucosal atrophy induced byfeeding rats an ED (Fig. 4) (Ref. 34) and stimulates mucosalgrowth in defunctionalized self-emptying jejunoileal loopsor isolated TVFs, thus supporting a direct role for NT in thestimulation of gut mucosal growth. These findings demonstratethat NT is an important trophic hormone that canmaintain and even augment gut mucosal structure by anincrease in overall mucosal cellularity. Consistent with ourfindings, Vagianos et al. (135) reported that NT restores gutFIG. 4. NT prevents small bowel mucosal atrophy associatedwith ED. Histology of Sprague-Dawley ratsmall bowel after ED, ED and NT (injected sc 300 g/kgthree times a day), and chow (control) for 5 d.Downloaded from edrv.endojournals.org by on July 16, 2007

580 Endocrine Reviews, October 2003, 24(5):571–599 Thomas et al. • Gastrointestinal Hormones and Proliferationmucosal integrity in rats and prevents the translocation ofindigenous bacteria after radiation-induced mucosal injury.We have extended the observation that NT increases proliferationof small bowel mucosa by evaluating the effects of NTin rats of different age groups and found that increases ofgrowth measurements (DNA, RNA, and protein) were thegreatest in the small bowel mucosa of aged rats. These findingsdemonstrate that, with aging, the ability of the smallbowel mucosa to respond to the trophic stimulus of NT isretained and may, in fact, be greater when compared with theproliferative response in young rats given NT.Izukura et al. (136) demonstrated that administration of NTaugments the normal adaptive hyperplasia of gut mucosathat is associated with massive (i.e., 70%) small bowel resection.Consistent with our results, de Miguel et al. (137) usedan 80% bowel resection model and demonstrated that exogenousNT significantly increased villus length in both thejejunum and ileum compared with the resected group notreceiving NT, suggesting that administration of exogenousNT potentiated the growth of the intestinal villi and acceleratedthe trophic response after massive small bowel resection.These investigators also noted increased circulatinglevels of enteroglucagon after NT administration and postulatedthat this may have contributed to the proliferativeeffect noted with NT. Ryan et al. (138) demonstrated in arabbit model of midgut bowel resection that either epidermalgrowth factor (EGF) or NT resulted in significantly increasedmicrovillus height and brush-border surface areas after administration.After bowel resection, both EGF and NT inducedenterocyte microvillus hypertrophy and increased absorptivesurface area in the remnant bowel. It was suggestedthat these peptides might be useful in accelerating smallbowel adaptation and preventing the development of shortbowel syndrome. The effects of NT on intestinal adaptationhave also been studied in a colectomy model (139). After acolon resection, jejunal proliferation increased significantlyin rats treated with NT, with less pronounced effects notedin the remaining colon and ileum. This study provides additionalsupport that NT augments the adaptive response ofeither the small bowel or colon after bowel resection.3. Colon. We have shown that NT (300 g/kg three timesdaily) stimulates proliferation of colonic mucosa in youngand aged rats in a differential fashion (41). Colonic proliferationin young (2-month-old) rats was characterized byincreases in cell number, whereas in aged (2-yr-old) rats,indices of hypertrophy were elevated significantly without aconcomitant increase in cell number. This study shows thatNT is not only important for small bowel growth and mucosalintegrity, but also functions as an important hormoneregulating colonic mucosal proliferation. Furthermore,Hoang et al. (134) demonstrated that NT (100 g/kg) significantlyincreased protein content in the colon but did notaffect weight or DNA content in F344 rats. The decreasedeffect noted in their study relates to the decreased dosage ofNT compared with our previous study. It is clear that, althoughnot as pronounced as the small bowel, NT can stimulateproliferation of colonic mucosa.4. Pancreas. Feurle et al. (40) demonstrated that administrationof NT increased pancreatic weight, DNA, RNA, andprotein contents as well as lipase and amylase concentrations.A proliferative effect for NT on the pancreas was likewisedemonstrated by Wood et al. (133) by chronic administrationof NT, which produced small but statisticallysignificant trophic effects in the pancreas, with the highestdose of NT (300 g/kg) increasing pancreatic weight by 16%,DNA content by 12%, and protein content by 17%. When NTwas given in combination with either cerulein or secretin, ithad minimal additive effects on the responses of these twopeptides (134). Therefore, from these studies it can be concludedthat NT stimulates pancreatic growth but not to thesame extent as CCK or BBS/GRP.E. PYYPYY inhibits blood flow to the GI tract (140, 141), inhibitssmall bowel fluid and electrolyte secretion (142–144), andregulates GI motility. In addition, administration of PYY canstimulate proliferation of small bowel and colonic mucosa.The effects of PYY on the stomach and pancreas are notknown.1. Small bowel and colon. Gomez et al. (51) first demonstrateda trophic effect for PYY (150–200 nmol/kg, three times daily)on the small bowel and colonic mucosa of both rat andmouse. Consistent with these findings, Chance et al. (145)found that PYY treatment (1 nmol/kgh) in Sprague-Dawleyrats given TPN produced significant increases in jejunal,ileal, and colonic protein contents.The trophic effects noted for PYY were in contrast to workby Guan et al. (146) demonstrating that PYY, administered at400 pmol/kgh (continuous infusion) for 4 d, failed to affectduodenal weight, protein, or DNA/RNA contents in maleWistar rats. In addition, using either a small bowel resectionmodel (147) or a gut atrophy model induced by TPN (148),administration of PYY failed to elicit a trophic effect on smallbowel mucosa. These negative results were attributable tothe smaller doses and different experimental designs.F. GLP-2A trophic effect for proglucagon-derived peptides(PGDPs) on the intestinal mucosa has been postulated sincethe description of a glucagon-secreting tumor of the kidneyassociated with small bowel mucosal hypertrophy. Druckeret al. (149) were the first to demonstrate that the intestinotrophicfactor was GLP-2.1. Small intestine. To assess the potential consequences ofincreased proglucagon gene expression on intestinal growth,Brubaker et al. (150) created glucagon-SV40 T-antigen transgenicmice that developed proglucagon-producing tumorsand elevated levels of the PGDPs. Small bowel mucosal hypertrophywas noted in the transgenic mice; however, it wasnot possible to ascertain which of the PGDPs was responsiblefor small bowel growth. To better ascertain which of thePGDPs stimulated gut growth, nude mice with three differentsc proglucagon-producing tumor xenografts (InR1-G9,RIN1056A, and STC-1 cells) were analyzed (149). Furthermore,CD1 mice were treated with GLP-1, GLP-2, glicentin,and intervening peptide (IP)-1 (all are produced from theDownloaded from edrv.endojournals.org by on July 16, 2007

Thomas et al. • Gastrointestinal Hormones and Proliferation Endocrine Reviews, October 2003, 24(5):571–599 581proglucagon gene). Mice with all three xenograft types demonstratedan increase in small bowel weight, crypt-villusheight, and percentage of BrdU-positive cells; glicentin (43.75g) administered twice daily for 10 d produced modest increasesin total small bowel weight. Neither GLP-1 nor IP-1had an effect on the gut mucosa, whereas GLP-2 produceda 50% increase in small bowel weight. Furthermore, onlyGLP-2 produced a significant increase in mucosal thickness,with the increase attributable to increased villus height (149).Similarly, Ghatei et al. (151) demonstrated prominent trophiceffects of GLP-2 in Wistar rats. Using varying doses of enteroglucagon,GLP-1, oxyntomodulin, and GLP-2, onlyGLP-2 produced a dose-dependent increase in the weight ofstomach, small intestine, and colon of parenterally fed rats.Therefore, these studies confirmed that, of the PGDPs, GLP-2was the major mediator of intestinal epithelial proliferation.Litvak et al. (152, 153) demonstrated that GLP-2 (1.75g/kg twice a day) significantly increased the weight ofjejunum, ileum, and colon of athymic nude mice comparedwith both control mice and mice treated with NT (600 g/kgthree times a day). These studies confirmed the previousfindings of a trophic effect for GLP-2 and demonstrated thatthe proliferative effects were equal to or greater than thoseof NT. In another study, GLP-2-producing tumor cells (STC-1cells) were implanted in athymic mice and then randomizedto receive either NT or saline (152, 153). The mice treated withNT and GLP-2 (from STC-1) displayed significant increasesin jejunal and ileal weight and protein content over either NTor GLP-2 alone. The administration of NT appeared to enhancethe enterotrophic effects of GLP-2, suggesting that thecombination may be useful to enhance intestinal growth inpatients with short bowel syndrome.In addition to the effects of GLP-2 on normal mucosa, theeffects of this agent during periods of gut injury or atrophyhave also been assessed. Mice treated with the nonsteroidalagent indomethacin develop small bowel enteritis associatedwith significant mortality at 48–72 h after administration;treatment with human [Gly 2 ]GLP-2 before, during, or afterindomethacin administration resulted in reduced mortalityand decreased mucosal injury (154). The protective effectswere attributed to significantly increased crypt cell proliferationand decreased crypt compartment apoptosis. Theeffect of GLP-2 on chemotherapy-induced intestinal mucositishas also been assessed. Pretreatment of mice with human[Gly 2 ]GLP-2 before administration of the topoisomerase inhibitoririnotecan resulted in reduced bacterial infection, intestinaldamage, and mortality (155). Histological and biochemicalanalyses revealed significant reductions in cryptcompartment apoptosis and reduced caspase-8 activation.Consistent with these reports, Tavakkolizadeh et al. (156)noted decreased intestinal damage in rats given GLP-2 incombination with the chemotherapeutic agent 5-fluorouracil.Finally, repeated cyclical administration of both human[Gly 2 ]GLP-2 and irinotecan resulted in decreased mortalityin groups of BALB/C mice implanted with sc CT-26 coloncarcinomas. These data suggest that GLP-2 may have therapeuticadvantages for cancer patients by supporting bowelintegrity without diminishing the effectiveness of thechemotherapy.2. Colon. Although the small bowel is significantly moresensitive to the effects of GLP-2, studies have shown thatGLP-2 and GLP-2 analogs can stimulate the growth of colonicmucosa. As previously noted, Litvak et al. (152) demonstrateda trophic effect of GLP-2 on the colonic mucosa ofathymic nude mice. Drucker et al. (157) demonstrated anincrease in colonic growth using dipeptidyl peptidase IVresistantGLP-2 analog, human [Gly 2 ]GLP-2 in CD1 mice.Furthermore, the combination of this agent with IGF-I, GH,or long [Arg3]IGF-I produced a greater increase in largebowel mass than mice treated with [Gly 2 ]GLP-2 alone.Treatment with GLP-2 has also been shown to reducecolonic mucosal injury, similar to the findings in the smallbowel (51). In a dextran sulfate-induced colitis model, concomitantadministration of sc human [Gly 2 ]GLP-2 and oraldextran sulfate for 10 d resulted in markedly reduced colonicdamage and decreased weight loss in CD1 and BALB/Cmice. Treatment with [Gly 2 ]GLP-2 preserved colonic length,decreased intestinal histological damage, reduced IL-1 expression,and increased crypt cell proliferation.G. SomatostatinSomatostatin has predominantly inhibitory effects, whichhave been used to advantage in certain clinical scenarios.Somatostatin inhibits pancreatic and GI secretion and GImotility and inhibits the release of GH and all known GIhormones (3). The active peptide analog of somatostatin(octreotide) has been effectively used as an agent to amelioratesymptoms associated with endocrine-overproducingtumors, pancreatic fistulas, and enterocutaneous fistulas(158, 159). In experimental studies, somatostatin has alsobeen shown to inhibit the growth of the GI mucosa andnormal pancreas (158, 159). These effects may be througheither an indirect mechanism such as inhibition of othertrophic hormones or a direct effect through interaction withthe somatostatin receptor subtype 2 (160, 161). This somatostatinreceptor subtype associates and stimulates tyrosinephosphatase src homology 2-containing tryosine phosphatase1 activity, which in turn arrests cells in the G o /G 1 phaseof the cell cycle associated with up-regulation of thecyclin-dependent kinase inhibitor p27 kip1 and an increase inhypophosphorylated retinoblastoma protein levels (160,161). Although the major portion of this review has focusedon the stimulatory effects of various GI hormones, it is importantto discuss the inhibition of growth using somatostatinand its analogs.1. Stomach. The effects of somatostatin on gastric mucosalgrowth have been assessed. Treatment of Wistar rats withsomatostatin (50 g/kgh) reduced nuclear uptake of[ 3 H]thymidine and cell division in both fundic and antralprogenitor cells (162). Furthermore, the combination of somatostatinand gastrin reduced gastrin-stimulated DNA synthesisin the gastric mucosa. In contrast, in the duodenumand jejunum, the effects of somatostatin were less consistent,with nocturnal somatostatin producing slight decreases inDNA synthesis. These findings suggested that somatostatincould inhibit cell proliferation in the mucosa of the normalGI tract and, furthermore, could antagonize the trophic ac-Downloaded from edrv.endojournals.org by on July 16, 2007

582 Endocrine Reviews, October 2003, 24(5):571–599 Thomas et al. • Gastrointestinal Hormones and Proliferationtivity of gastrin, particularly in the fundus and antrum of thestomach. Similar results were noted by Rivard et al. (61),demonstrating inhibitory effects on rat mucosal growth ofthe duodenum using the somatostatin analog, Sandostatin.The administration of Sandostatin in this model was associatedwith a decrease in plasma CCK and IGF-I levels (61),suggesting an induced effect of somatostatin.2. Small intestine. There is also evidence to support an inhibitoryeffect of somatostatin in the jejunum and ileum. Bass etal. (62) demonstrated that the normal adaptive hyperplasianoted in rats after 40% small bowel resection could be attenuatedby administration of octreotide, as noted by assessmentof villus height and residual bowel weight. Using arabbit model of an ileal mucosal defect, Thompson et al. (163)demonstrated that octreotide inhibited normal but not EGFstimulatedcell migration. In addition, octreotide decreasedEGF-stimulated proliferation. In contrast, Vanderhoof andKollman (164) failed to show significant differences in mucosalweight, protein, and sucrase levels in rats treated withoctreotide after an 80% small bowel resection. The differencesnoted in this study, compared with that of Bass et al.(62), may simply represent the fact that a more extensiveresection model was used, which may have provided anenhanced stimulation of mucosal regeneration that could notbe inhibited by administration of somatostatin.The question remains, however, as to the role endogenoussomatostatin plays in the inhibition of normal intestinalgrowth and proliferation. Parekh et al. (63) demonstrated thatsomatostatin appears to function as an endogenous inhibitoryfactor. Male F344 rats were given cysteamine (CYS; anagent known to deplete endogenous somatostatin). The administrationof CYS stimulated growth of the proximal anddistal small intestine as assessed by increases in weight,DNA, and RNA content; this effect was assumed to be secondaryto a depletion of endogenous somatostatin, althoughother indirect effects cannot be entirely ruled out.3. Pancreas. The effects of somatostatin on the normal pancreashave been extensively analyzed. The finding of Dcells in the normal pancreas suggested a role for this peptidein not only physiological functions of the pancreas,but also growth of the normal pancreas. Rivard et al. (61)demonstrated that Sandostatin significantly decreasedpancreatic weight, DNA, RNA, and protein content. Furthermore,results of Parekh et al. (63) demonstrated thatsomatostatin depletion with CYS stimulated pancreaticweight by 127% and DNA content by 141% compared withcontrol animals. In addition, CYS augmented the trophiceffect of BBS on the pancreas, thus suggesting that somatostatinmay serve to limit normal pancreatic growth.Blocking endogenous somatostatin may release these inhibitoryconstraints and allow for increased proliferationof the normal pancreas. The specific mechanisms, however,as to how somatostatin acts in vivo are still unknown.The effects may be direct, acting through the somatostatinreceptor subtype 2 receptor, or indirect through the inhibitionof other proliferative agents.IV. Proliferation of Neoplastic Tissues byGI HormonesEndocrine control of cancer growth was first demonstratedby the Scottish surgeon Beatson (165), who successfullytreated a patient with breast cancer by performing bilateraloophorectomy. In 1941, Huggins and Hodges (166)described orchiectomy and estrogen therapy for patientswith prostate cancer, and then, in 1952, Huggins and Bergenstal(167) performed bilateral adrenalectomy, whichcaused regression of breast and prostate cancers in certainpatients. In 1971, Jensen et al. (168) reported that the presenceof estrogen receptors predicted response to adrenalectomyfor patients with breast cancer. Therefore, the response ofbreast and prostate cancers to endocrine therapy is wellestablished and forms the basis of many of the current therapeuticoptions described for the treatment of these cancers.In a manner analogous to breast and prostate cancers, thehypothesis was formulated that GI cancers may also possessreceptors and likewise be responsive to various GI hormones.In this regard, receptors for various GI hormoneshave been identified in gastric, pancreatic, and colorectalcancers; these cancers are responsive to the effects of GIhormone treatment (169).A. Gastric cancerAlthough the incidence of gastric cancer has been decreasingin the United States, it is still estimated to be one of themore common cancers worldwide and is endemic in certainareas of the world such as Japan, Eastern Europe, and SouthAmerica (170). The therapeutic options are limited, becauseradiation and chemotherapy are, for the most part, ineffectivein increasing survival in patients with metastatic disease(170).Certain gastric cancers possess both low- and high-affinitygastrin/CCK-B receptors (171, 172). The growth of thesecancers is stimulated by pharmacological and, in certain instances,physiological concentrations of gastrin or gastrinanalogs in vitro and in vivo (173–178). Sumiyoshi et al. (174)identified gastrin receptors in the human gastric cancer, SC-6-JCK; treatment of this poorly differentiated adenocarcinomawith gastrin resulted in increased tumor weight, size,and labeling index of [ 3 H]thymidine. Gastrin receptor antagonistsblocked these trophic effects, demonstrating a directeffect through the gastrin/CCK-B receptor (174, 179).Other therapeutic strategies that decrease gastrin receptorpositivegastric cancer growth include inhibition of gastrinrelease by agents such as enprostil, a prostaglandin derivativethat lowers serum gastrin levels in fasted and fed humansand mice. Administration of enprostil to mice bearinggastrin receptor-positive gastric cancers inhibited the growthof these cancers; however, the growth of gastrin receptornegativecancers was not affected (180). Therefore, these findingsindicate that certain gastric cancers possess gastrin receptors,and growth may be modulated by either blockingthe receptors or inhibiting gastrin release.The glycine-extended G-17 peptide, Gly-G, which is colocalizedwith amidated gastrin in antral G cells and cosecretedwith G-17, was initially thought to be biologicallyDownloaded from edrv.endojournals.org by on July 16, 2007

Thomas et al. • Gastrointestinal Hormones and Proliferation Endocrine Reviews, October 2003, 24(5):571–599 583inactive. However, Iwase et al. (181) have shown that Gly-Gstimulated the growth of the human gastric cancers, AGS andSIIA. This increased growth was not blocked by either theCCK-B or the CCK-A receptor antagonists, suggesting thepresence of a novel receptor that is different from the classicCCK-A or CCK-B receptor. In contrast, G-17 stimulated thegrowth of both AGS and SIIA cells. Consistent with thesefindings, Szabo et al. (182) demonstrated stimulation of AGScell growth with both G-17 and pentagastrin. Pentagastrinwas found to be 10 times less potent as a stimulator of AGSproliferation when compared with G-17, suggesting a specific,active CCK-B/gastrin receptor in these cells.Although the effects of gastrin appear well established intumor models, the effects of gastrin on carcinogen-inducedgastric cancers have produced conflicting results. Tahara andHaizuka (183) noted that gastrin increases the incidence ofN-methyl-N-nitro-N-nitroguanidine (MNNG)-induced cancersin rats, whereas Tasuta et al. (184) found that gastrininhibits the incidence of stomach cancers induced by thesame carcinogen. The timing and administration of gastrinappears critical in these two studies and may account for theconflicting results. For example, it was noted that gastrinadministered during exposure to MNNG increased gastriccancer development, but late administration did not displaythe same growth-enhancing effect. Therefore, the effects ofgastrin may be more pronounced in the early stages of tumordevelopment rather than in the later stages of growth inwhich other peptide factors may play a more prominent role.Recent findings by Hagiwara et al. (185) further support a rolefor gastrin in carcinogen-induced stomach cancers. In thisstudy, carbachol-induced glandular carcinomas in F344 ratswere associated with increased endogenous gastrin levels.In addition to experimental studies, clinical studies furtherlink gastrin to the development and growth of gastric cancers.Recently, gastrin has been linked to Helicobacter pyloriinfection, a known risk factor for gastric cancer (186). Moreover,significantly higher plasma and luminal gastrin levelshave been measured in gastric cancer patients comparedwith control patients (186). Watson and colleagues (173, 187)evaluated 90 archival samples of atrophic gastritis; intestinalmetaplasia; mild, moderate and severe gastric epithelial dysplasia;and intestinal-type gastric adenocarcinoma. Increasedexpression of gastrin and the CCK-B/gastrin receptor wasassociated with the progression of atrophic dysplasia to adenocarcinoma(173). Together, these clinical studies providefurther support, albeit circumstantial, for the role of gastrinin gastric carcinogenesis.In addition to gastrin, GRP is thought to contribute togastric cancer growth. Preston et al. (188) identified highaffinityGRP receptors in a single gastric cancer cell line, St42,and Kim et al. (189) identified expression of GRP receptors intwo in vitro gastric cancer cell lines (SIIA and MKN-45) andin three of five human gastric cancer xenografts. The presenceof GRP receptors in gastric cancer appears to play afunctional role in the growth of these tumors, as noted by Qinet al. (190) who demonstrated that the GRP receptor antagonist,RC-3095, blocked the growth of the human gastriccancer, Hs746T, both in vitro and when placed as xenograftsin nude mice. Pinski et al. (191) also found that RC-3095significantly inhibited MKN-45 xenograft tumor weight andvolume. As an assessment of signaling pathways regulatingthe mitogenic effect of GRP, Kim et al. (189) from our laboratoryhave shown that treatment of the gastric cancer cellline, SIIA, with BBS stimulates release of intracellular calciumand increases the expression of the activator protein(AP)-1-related proteins, c-Jun and c-Fos, that have beenshown to play a role in cellular proliferation; this effect wasblocked by specific GRP receptor antagonists. Clinical studiesindicate that as many as 50% of gastric cancers displayhigh-affinity binding for GRP (192). Similarly, Carroll et al.(193) identified expression of GRP receptor mRNA in eightof 20 (40%) nonantral gastric cancers. Of these eight, six of theGRP receptors were mutated; some of the mutations resultedin nonfunctional GRP receptors. Survival of patients whosetumors expressed functional GRP receptors was not statisticallydifferent from those that did not; however, this mayrepresent the fact that only a small number of patients wereanalyzed. Future studies, assessing a larger patient population,are required before a definitive assessment can be maderegarding the association of GRP receptors with gastriccancers.Finally, in limited studies, the hormone NT has beenshown to contribute to carcinogen-induced gastric cancer.Tatsuta et al. (194) found that prolonged alternate-day administrationof NT significantly increased the incidence ofMNNG-induced gastric cancer in Wistar rats compared withrats given MNNG alone. The effect of NT on human gastriccancers, however, has not been assessed.B. Pancreatic cancerCarcinoma of the pancreas is the fifth leading cause ofcancer deaths in the United States (195). The prognosis fromthis disease remains dismal, with a mean survival time afterdiagnosis of about 4–6 months. The effects of both stimulatoryand inhibitory hormones on pancreatic cancer growthhave been assessed, and the signaling mechanisms regulatinghormone-induced pancreatic cancer proliferation are currentlybeing analyzed.Experimental studies have demonstrated a role for CCKand gastrin in pancreatic cancers. CCK receptors have beenidentified in hamster and human pancreatic cancer cell lines.In vitro studies have demonstrated that CCK and its analog,JMV-180, can stimulate the growth of human pancreatic cancercell lines, including MIA PaCa-2 (196–199), PANC-1 (197,199, 200), BxPC-3 (198, 199), Capan-2 (199), RWP-2 (199),SW-1990 (199, 201, 202), and MD PANC-3 (203). Similarly, thepresence of CCK receptors can predict the responsiveness ofhuman pancreatic cancer cells to CCK treatment (180, 204,205). In addition to effects on pancreatic cancer proliferation,Hirata et al. (206) reported that CCK-8 increases the productionof metalloproteinase-9 in pancreatic cancer cells via inductionof protein kinase C, suggesting a role for CCK inpancreatic cancer invasiveness and possibly metastasis.Cerulein, a CCK analog, significantly stimulates thegrowth of the CCK receptor-positive pancreatic cell line SKI(207); however, cerulein has no effect on the CAV pancreaticcancer cell line, which does not possess CCK receptors.Furthermore, Asperlin, a competitive, nonpeptide CCK receptorantagonist, inhibits growth of SKI xenografts (208).Downloaded from edrv.endojournals.org by on July 16, 2007

584 Endocrine Reviews, October 2003, 24(5):571–599 Thomas et al. • Gastrointestinal Hormones and ProliferationTownsend et al. (209) demonstrated that growth of the hamsterpancreatic cancer cell line, H2T, was stimulated by ceruleinand that growth could be further enhanced by concomitanttreatment with secretin. Both gastrin and Gly-G canstimulate the proliferation of AR42J rat pancreatic tumorcells (210, 211); these growth-promoting effects can beblocked by L-365,260, a CCK-B receptor antagonist (210–212). Therefore, these studies provide strong support for amodulatory effect of CCK, secretin, and gastrin on certainpancreatic cancers. In contrast, Liehr et al. (213) found thatCCK, at dosages of 10 12 to 10 6 m, had no effect on thegrowth of either MIA PaCa-2 or PANC-1 cells. Moreover,stable transfection of MIA PaCa-2 and PANC-1 cells withCCK-A or CCK-B receptors resulted in growth-inhibitoryresponses after activation of both receptor subtypes by theirligands. The reason for these discrepant results is not readilyapparent.In vivo studies support a role for CCK in the stimulationof pancreatic cancer growth. Pancreatic tumors in rats can beinduced by endogenous CCK using CCK-releasing agents,such as trypsin inhibitors, by biliary diversion or using bilesalt-binding drugs (214–216). For example, feeding rats asoybean diet, a natural trypsin inhibitor, induced the formationof preneoplastic lesions in the pancreas and, whentreatment was prolonged for years, pancreatic cancer developed(217–219).Evidence exists that CCK can enhance chemical carcinogen-inducedpancreatic cancers, as well. When combinedwith azaserine (a carcinogenic DNA alkylating agent), thelong-term administration of exogenous CCK or elevation ofendogenous CCK levels (220–222) enhanced the developmentor shortened the latency period of the preneoplasticacinar lesions. These effects could be blocked by CCK-Areceptor antagonists (223–225). Consistent with these results,Satake et al. (107) found that administration of ceruleinenhanced the carcinogenic effect of N-nitrosobis (2-hydroxypropyl) amine in hamsters. Furthermore, Howatsonand Carter (226) found that both CCK and secretin enhancedpancreatic carcinogenesis induced by N-nitrosobis (2-oxypropyl) amine (BOP) in hamsters. In contrast, Johnsonet al. (227) reported that CCK-8 inhibited development ofnitrosamine-induced pancreatic cancer in hamsters. The differencesnoted in these studies may relate to differences in theanimal models. With the exception of this study, the majorityof studies suggest that agents capable of increasing endogenousCCK and stimulating the growth of normal pancreascan also stimulate pancreatic carcinogenesis.Similar to CCK, BBS/GRP, another pancreatic trophic factor,has been associated with pancreatic carcinogenesis.Douglas et al. (223) demonstrated that rats treated with azaserine(30 mg/kg) and BBS (10 mg/kg) for 16 wk developedpreneoplastic lesions at a higher rate than rats treated withazaserine alone. Similar results were noted by Meijers et al.(228) and Lhoste and Longhecker (208). This effect was notmediated solely by induction of CCK because the developmentof preneoplastic lesions was not blocked by the CCKreceptor antagonist CR-1409 (223). In contrast, another studydemonstrated that administration of BBS was accompaniedby a decrease in the number of preneoplastic lesions in BOPtreatedhamsters. The differential effects of BBS in thesestudies may be attributed to species differences and also tothe differences in the carcinogenic agents.In another study, Szepeshazi et al. (229) demonstratedthat administration of the BBS receptor antagonist, RC-3095, decreased BOP-induced pancreatic cancers in hamsters.RC-3095 significantly decreased EGF binding capacity,suggesting that indirect effects might be largelyresponsible for the reduction identified in BOP-associatedhamster cancer. In a subsequent study (230), these investigatorsshowed that the combination of GRP or BBS withRC-3095 was not able to overcome the effects of RC-3095but, conversely, augmented the inhibitory effects of RC-3095. These data are more consistent with the observationsof Meijer and Baak (231) in hamsters and show the complexityof BBS/GRP regulation in pancreatic cancer, whichmay be highly species-dependent.More recently, the effects of a potent and specific GRPreceptor antagonist, BIM 26226 [[d-F5 Phe 6, d-Ala 11] BBS(6–13) OMe], were evaluated in pancreatic cancers in vivoand in vitro (232). Chronic BIM 26226 administration significantlyreduced tumor volume, protein, RNA, amylase, andchymotrypsin content in both GRP-responsive and GRPunresponsivepancreatic cancers. These findings suggest thatGRP receptor antagonists may work through either a director indirect effect to inhibit tumor growth. Furthermore, arecent study by Burghardt et al. (233) demonstrated that BBSincreases expression of three transcription factors (c-fos,c-myc, and high-mobility group protein IY) that are associatedwith proliferation in the human pancreatic cell lineHPAF. These results provide potential novel mechanisms fortargeting the trophic effects of BBS/GRP in pancreaticcancers.Similar to CCK, NT also stimulates pancreatic cancer proliferation.Our laboratory has shown that the human pancreaticcancer cell line MIA PaCa-2 possesses NTRs and mobilizesintracellular calcium (234). Iwase et al. (181) haveshown that the NTR antagonist SR48692 inhibits intracellularcalcium mobilization, IP-3 turnover, and MIA PaCa-2 in vitrocell growth induced by NT in a dose-dependent fashion.Furthermore, in vivo experiments demonstrated that NT significantlyincreased the size, weight, and DNA and proteincontents of xenografted MIA PaCa-2 tumors; SR48692blocked this effect. Recent findings by Reubi et al. (235) haveshown that approximately 75% of pancreatic adenocarcinomasexpress NTRs. Consistent with these reports, Ehlers et al.(236) have shown NTR expression in approximately 90% ofresected pancreatic cancers.The signaling mechanisms regulating NT-mediated proliferationin NTR-positive cancers have been assessed. NTstimulates ERK and JNK activity in MIA PaCa-2 cells andincreases AP-1 binding activity (237). Consistent with theseresults, Ryder et al. (238) reported that NT stimulated Ca 2mobilization and activated ERK1 and ERK2 and DNA synthesisin the human pancreatic cancer cell line, PANC-1.Recently, Guha et al. (239) reported that NT induced a rapidactivation of the PKC isoform, PKD, in PANC-1 cells, whichwas linked to the mitogenic effect of NT.The effects of PYY on pancreatic cancer growth have beenexamined. Treatment of the human pancreatic cancer celllines, MIA PaCa-2 and PANC-1, with the synthetic analog ofDownloaded from edrv.endojournals.org by on July 16, 2007

Thomas et al. • Gastrointestinal Hormones and Proliferation Endocrine Reviews, October 2003, 24(5):571–599 585PYY, PYY 22–36, inhibited the growth of these cells in vitro(240). A significant decrease in the growth of human pancreaticcancer xenografts was demonstrated in nude micegiven PYY 22–36 for 2 wk (241). Similarly, there was a decreasein cyclic adenosine monophosphatase expression andaugmentation of the tumor-suppressing capability of 5-fluorouracil and leucovorin (241, 242). More recently, Liuet al. (243) reported that a biotinylated PYY analog 14–36,linked to a fluorescent dye attached to streptavidin, significantlybound to human pancreatic cancer cells MIA PaCa-2and PANC-1 and inhibited the growth of these pancreaticcancer cells. It was postulated that biotinylated PYY 14–36could be used to selectively deliver toxic agents to the cancersor, conversely, as a diagnostic tool tagged with a fluorescentagent to identify the extent of disease. The results of thesestudies suggest that PYY can inhibit pancreatic cancergrowth. However, it has not been determined whether amajority of pancreatic cancers express receptors for PYY.Also, the cellular mechanisms for the inhibitory effect of PYYneed to be better delineated.Similar to PYY, somatostatin and its analogs have beenevaluated as antiproliferative agents in the treatment of pancreaticcancer. Many pancreatic cancers have high-affinitybinding sites for somatostatin (244, 245); however, the precisemechanisms regulating the antiproliferative effect of somatostatinhave not been entirely elucidated. Potential mechanismsinclude a direct receptor-mediated effect and possiblyan indirect effect that could include inhibition ofangiogenesis and/or the suppression of GH and IGF secretion(244, 245). Redding and Schally (246) reported significantreductions in tumor weight and volume in Wistar-Lewisrats bearing the pancreatic acinar tumor DNC-322 after a21-d administration of somatostatin analog [l-5-Br-Trp 8 ]somatostatin-14.Upp et al. (64) demonstrated inhibition of twohuman pancreatic cancer xenografts (SKI and CAV) in nudemice by the administration of the long-acting somatostatinanalog SMS 201-995 (octreotide). Other growth factors (e.g.,EGF) may modulate the growth of pancreatic cancers. In vitrostudies by Hierowski et al. (247) and Liebow et al. (248)demonstrated receptors for EGF and somatostatin in the MIAPaCa-2 cancer cell line. The effects of somatostatin may bethrough its actions on other growth factors and their receptors.For example, the long-acting analog RC-160 inhibitsproliferation of the pancreatic cancer cell line MIA PaCa-2,possibly by activating dephosphorylation of the EGF receptor(247, 248).Colorectal cancer is a significant health problem worldwide,with the death rate remaining third to lung and prostatecancer in men and lung and breast cancer in women(249). Approximately 57,000 deaths are expected to occur thisyear in the United States (249). Current chemotherapeuticregimens are relatively ineffective for metastatic disease. Theeffects of GI hormones, particularly gastrin, have been welldescribed and characterized in various colon cancer models.Gastrin stimulates the growth of colorectal cancers thatpossess high-affinity gastrin receptors, including the mousecolon cancer cell line MC-26. The administration of the gastrinreceptor antagonist, proglumide, inhibited the growth ofMC-26 tumors in vivo and prolonged survival of tumorbearingmice (Fig. 5) (250). Ishizuka et al. (251) have shownthat gastrin stimulates the growth of two human colon cancercell lines, LoVo and HT29, but inhibits the growth of a thirdcolon cancer cell line, HCT-116, suggesting that differentgastrin receptor subtypes or other signal transduction pathwaysregulate the trophic effects of gastrin. As an alternateapproach, we have assessed the effect of suppressing endogenousgastrin with the prostaglandin analog enprostil onMC-26 tumor growth and found that, similar to our resultsin gastric cancers, enprostil significantly inhibited MC-26tumor growth in vivo (252, 253).In addition to the experimental evidence for the effect ofgastrin on colon cancers, clinical studies have assessed thepotential role of gastrin and gastrin receptor expression incolorectal tumors. Upp et al. (254) analyzed 67 primary colorectalcancers for gastrin receptors and found a spectrum ofreceptor expression, suggesting a correlation between tumorstage and the presence of gastrin receptors. A significantlygreater percentage of patients (52%) with early cancers(Dukes’ A and B) had gastrin receptor contents greater than10 fmol/mg when compared with patients with more advancedcolorectal cancers (Fig. 6). In contrast, five of 19Dukes’ C patients and eight of 16 Dukes’ D patients withgastrin receptors less than 10 fmol/mg protein developedtumor recurrence or died. This study was the first to suggestthat assessment of gastrin receptor expression in colorectalcancers may predict tumor stage as well as overall survival.Further studies are needed to correlate the receptor expressionwith long-term clinical parameters.Hoosein et al. (255, 256) demonstrated that gastrin stimulatescolorectal cancer cell growth and that this stimulationwas possibly attributable to an autocrine mechanism. Thegrowth of six colon cancer cell lines was assessed after treatmentwith two gastrin receptor antagonists, proglumide andbenzotript, or antibodies to gastrin (255). Both inhibitorssuppressed monolayer cell growth in all of the colon cancerlines. Furthermore, in HCT-116 cells, the addition of antigastrinantisera resulted in a concentration-dependent inhi-C. Colorectal cancerFIG. 5. Survival of MC-26 tumor-bearing mice after treatment withnormal saline (solid line), proglumide beginning on the day of tumorinoculation (long-dash line), or proglumide beginning 7 d after inoculation(short-dash line). [From R. D. Beauchamp et al.: Ann Surg202:303–309, 1985 (250).]Downloaded from edrv.endojournals.org by on July 16, 2007

586 Endocrine Reviews, October 2003, 24(5):571–599 Thomas et al. • Gastrointestinal Hormones and ProliferationFIG. 6. Gastrin receptor (GR) content by stage of disease. A, Numberof patients with tumors highly positive for gastrin receptors (10fmol/mg protein) and either negative or poorly positive (10 fmol/mgprotein) for receptors, by stage of disease. B, Percentage of patientswith tumors demonstrating more than 10 fmol gastrin receptors (GRper milligram protein) by stage of disease. *, P 0.05. [Reproducedwith permission from J. R. Upp Jr. et al.: Cancer Res 49:488–492,1989 (254).]bition of cellular proliferation in serum-free media. Next,proliferation of the colon cancer cell lines HCT-116 and CBSwas assessed using dibutyryl cyclic GMP (cGMP), a gastrinreceptor antagonist (256). Dibutyryl cGMP inhibited proliferationand induced morphological change in both cell lines.In binding studies, dibutyryl cGMP competed with 125 I-labeled gastrin for binding to HCT-116 cells (IC 50 , 1.8 mm).RIA of conditioned media from both cell lines demonstratedthe presence of gastrin. Additionally, Northern blot analysisdetected expression of gastrin mRNA.Additional studies provide support for the potential autocrinerole of gastrin in colorectal cancer growth. Smith andWatson (257) found no expression of gastrin or gastrin/CCK-B receptors in normal colonic mucosa although demonstrating78 and 81% expression, respectively, in colonicpolyps. Immunohistochemical analysis identified progastrinin 91% of polyps, Gly-G in 80%, and G-17 in only 47%. Thisstudy was the first to demonstrate widespread expression ofboth gastrin and its receptor in preneoplastic colorectal polyps,suggesting that gastrin may promote tumor progressionthrough the adenoma-carcinoma sequence in the colon. Becausea majority of human colon cancers express the gastringene (258), it was suggested that expression of gastrin maybe critically linked to gastrin-controlled growth of cancercells. This supposition was further supported by the demonstrationthat antisense RNA to the gastrin gene inhibitedthe growth of Colo-320 and HCT-116 colon cancer cells,which express gastrin, whereas the growth of Colo-205Acells, which do not express gastrin, was not affected by antisensetreatment (66).Although the proliferative effects of exogenous gastrin ongastrin-receptor positive colorectal cancers have been demonstratedin numerous in vitro and in vivo models, the rolesof endogenous hypergastrinemia and colon carcinogenesisare controversial. McGregor et al. (259) found that antralexclusion, which produces a profound hypergastrinemia,increased DNA synthesis and carcinogen-induced colon tumorsbut did not alter the incidence of tumor formation. Incontrast, Oscarson et al. (260) demonstrated that endogenoushypergastrinemia, induced by fundectomy, did not potentiatedimethylhydrazine (DNH)-induced colon carcinogenesis.The discrepancies between these studies may be relatedto the timing and administration of the carcinogen as well asthe method of producing hypergastrinemia.In addition, there remains considerable confusion regardingthe forms of gastrin that are responsible for the regulationof human colorectal cancer growth. For example, Kameyamaet al. (261) reported that the incidence of liver metastasis incolorectal cancer was significantly higher in patients withelevated serum gastrin levels. Thorburn et al. (262) conducteda case control study among 128,992 subscribers to a healthmaintenance program and found that median gastrin levelswere similar in patients with colorectal cancers and matchedcontrols (41.7 vs. 40.7 pg/ml). However, elevated gastrinlevels were associated with increased risk of colorectal malignancy(odds ratio, 3.9). These authors concluded that thisrelationship was causal, with 8.6% of colorectal cancers thatcould be attributed to hypergastrinemia. Other studies havedemonstrated increased circulating levels of gastrin in somepatients with colorectal cancer but little or no change inothers (263–265).There is increasing evidence that Gly-G and the lessprocessedprogastrin peptides, the so-called nonamidatedgastrins, may be the critical regulator of colorectal cancergrowth. Siddheshwar et al. (266) found elevated levels ofGly-G, but not G-17, in patients with colorectal cancer anddysplastic polyps. Stepan et al. (267) found that G-17 failedto bind or stimulate the growth of LoVo, HT29, HCT-116,Colo 320DM, or T84 cells. In contrast, LoVo and HT29 cellsdisplayed saturable binding of Gly-G. Treatment with Gly-Gincreased proliferation of LoVo and HT29 cells as measuredby [ 3 H]thymidine uptake; these effects were not blocked byG-17 or the gastrin/CCK-B receptor antagonist, PD134308.These data suggest that Gly-G, binding to a novel receptor,plays a critical role in the growth of certain colon cancer cells.Similarly, Litvak et al. (268) found that Gly-G stimulatedgrowth of DLD-1 cancer xenografts in nude mice. Moreover,a novel gastrin-receptor antagonist, JMV1155, blocked thestimulatory effects of Gly-G.Additional support for a role of gastrins, other than the amidatedG-17 and G-34 gastrins, in colorectal cancer growth isprovided by findings in transgenic mice. Singh et al. (269, 270)evaluated the mitogenic induction and adenoma/adenocarcinomaformation after azoxymethane treatment in miceDownloaded from edrv.endojournals.org by on July 16, 2007

Thomas et al. • Gastrointestinal Hormones and Proliferation Endocrine Reviews, October 2003, 24(5):571–599 587overexpressing progastrin compared with wild-type mice andmice overexpressing G-17. Progastrin-overexpressing mice displayedincreased tumor formation and mitogenic indices comparedwith both wild-type and G-17-overexpressing mice.Recently, Siddheshwar et al. (266) found that progastrin, and notG-17, was elevated in patients with colorectal cancer and dysplasticpolyps, thus providing clinical support for the importanceof nonamidated gastrins.Most recently, the identification of a constitutively activevariant of the gastrin/CCK-B receptor is providing novelinsight into further effects of gastrin in the proliferation ofcolorectal cancers. Hellmich et al. (271) identified a CCK-Breceptor splice variant that is expressed only in colorectalcancers but not in normal colonic mucosa adjacent to thecancer. This splice variant exhibits constitutive (ligandindependent)activation of pathways regulating intracellular-freecalcium and cell growth. Primary cultures of cellsisolated from resected colorectal cancers exhibited spontaneous,ligand-independent oscillatory increases in intracellularcalcium, with an increase in intracellular calcium notedwith the addition of G-17. Selective CCK-B receptor antagonistsblocked the G-17-stimulated calcium stimulation butnot the spontaneous intracellular calcium oscillations. Cellsexpressing the CCK-B receptor splice variant exhibited anincreased growth rate in the absence of G-17 compared withcells stably transfected with the wild-type CCK-B receptor.The selective pattern of expression, the constitutive activityand trophic action associated with this CCK-B receptor splicevariant suggested that this novel variant may regulate colorectalcancer cell proliferation through a gastrin-independentmechanism. This splice variant has recently been identifiedin pancreatic cancers, suggesting that expression may not belimited to colorectal cancer (272).In addition to gastrin, NT stimulates growth of certainhuman colon cancer cell lines both in vitro and in vivo (273,274). Yoshinaga et al. (273) demonstrated that administrationof NT (either 300 or 600 g/kg, three times daily for 21 d)significantly stimulated mean tumor area, weight, and DNA,RNA, and protein content of the murine colon cancer, MC-26.In addition, the survival rate of mice bearing MC-26 tumorsand treated with NT was significantly decreased comparedwith the control group. Similarly, NT stimulated growth ofthe human colon cancer, LoVo. We have shown that approximately25% of colon cancers analyzed express NT mRNA(274). An autocrine effect for NT in certain colorectal cancersis postulated on the basis of NT expression in four colorectalcancer cell lines (LoVo, HT29, HCT-116, and CBS), one ofnine cancer xenografts, and two of six freshly resected coloncancers; NT expression was not identified in the adjacentnormal colonic tissue. NT peptide was detected in LoVo,HT29, and HCT-116 extracts; and NTR expression was demonstratedin HT29 and HCT-116 cells. In a study by Rovereet al. (275), all 13 human colon cancer cell lines displayed lowto moderate levels of pro-NT/neuromedin N protein expression.Only six of these 13 tumors, however, processed theprecursor to produce NT and larger precursor fragmentsending with the NT or neuromedin N sequence. Similar tothe signaling pathways mediating the effects of NT in pancreaticcancers, Ehlers et al. (276) have shown that NT treatmentof the human colon cancer cell line KM20, whichexpresses high levels of the NTR, results in calcium mobilizationas well as activation of the ERK pathway. Thesefindings suggest that the proliferative effect of NT may bethrough the ERK stimulatory pathway and that, similar togastrin, NT may be an autocrine growth factor in certaincolon cancers. The fact that intraluminal fats are the mostpotent stimulus for NT release suggests an association betweenthe known stimulatory effects of fats on colon carcinogenesisand hormones, such as NT, which increase coloncancer proliferation.Additionally, NT appears to promote carcinogenesis in thecolon of rats. Tatsuta et al. (184) reported that rats given10 weekly injections of azoxymethane (7.4 mg/kg), as well asNT (200 g/kg every other day for 40 wk), displayed significantincreases in the number and size of colon tumors,with a higher degree of submucosal penetration. This wascontrasted by the fact that NT alone did not increase theoverall incidence of colonic tumors in rats. NT caused asignificant increase in tumor cell modification above that ofnormal colonic mucosa.Similar to findings in gastric and pancreatic cancers, somatostatinhas been shown to inhibit growth of certain humancolon cancers (65–67). Our laboratory has found that thesomatostatin analog, MK-678, significantly inhibited growthof human colon cancer xenografts (RIP and DRUM) (277).One mechanism may be due to inhibition of gastrin release,which is further supported by the demonstration that administrationof octreotide blocked gastrin-induced stimulationof the MC-26 colon cancer cell line (65). Melen-Muchaet al. (278) have demonstrated that octreotide inhibits proliferation,as measured by BrdU, and increases apoptosis, asassessed by increased nuclear DNA fragmentation. Octreotidedecreases the proliferation/apoptosis ratio in favor ofcell death in Colon 38 transplanted tumors in mice. Inhibitionof colorectal cancer growth with somatostatin analogs hasnot been demonstrated in all cancer cell lines. di Paolo et al.(67) found that the somatostatin analog, SMS 201-995, inhibitedgrowth of SW480 colon cancer cells, but failed to alterthe growth of SW620 cells. However, SW620 cells were sensitiveto SMS 201-995 when used in combination with IL-1 orinterferon-. These results suggest the existence of differentsomatostatin receptor subtypes, which may account for differentialeffects of somatostatin analogs in colorectal cancercells. A recent study has found that linking toxic chemotherapeuticagents to somatostatin analogs that selectively bindto somatostatin receptor subtypes can direct chemotherapeuticagents and provide more efficient delivery of cytotoxicagents to colorectal tumors (279).D. Other cancersGI hormones have been shown to play trophic roles in neoplasmsoutside the GI tract as well. Notable examples includebreast, lung, and prostate cancers and neuroblastomas.1. Breast cancer. In 2002, of the 647,000 new cases of canceraffecting women in the United States, almost one third werebreast cancers, making breast cancer the most prevalent canceramong women (249). Hormonal therapy, with antiestrogenagents such as tamoxifen, is an important adjuvant agentDownloaded from edrv.endojournals.org by on July 16, 2007

588 Endocrine Reviews, October 2003, 24(5):571–599 Thomas et al. • Gastrointestinal Hormones and Proliferationin patients with estrogen receptor-positive cancers and maybe useful in prevention as well (280). Furthermore, Herceptin,a monoclonal antibody growth factor receptor that blocksthe Her-2/neu (c-erb-B2) growth factor receptor, a memberof the EGF receptor family, has recently been shown to be ofpotential benefit to patients with breast cancers that are positivefor Her-2/neu (280). Certain GI hormones have alsobeen shown to affect breast cancer growth.Goettler et al. (281) noted increased postprandial levels ofgastrin in women with stage I and II breast cancer. In contrast,levels of NT and CCK were not altered. This increasein gastrin was found to be independent of diet and suggestedthat hypergastrinemia may contribute to breast carcinogenesis.These findings are further supported by the occasionalexpression of gastrin in breast carcinomas (282). Neslandet al. (283) screened 38 infiltrating ductal carcinomas forgastrin and found scattered positive-staining cells for gastrinin five of 38 cases. An indirect mechanism for the effect ofgastrin has been postulated in breast cancers. Gastrinenhancedproteolysis leads to increased availability of tryptophan-derivedserotonin that, in turn, stimulates pituitaryrelease of prolactin (a central activator of breast development)and may contribute to breast cancer growth (281).Although limited and relatively circumstantial, these datasuggest that gastrin may play some role in breast cancerdevelopment or growth. More studies are warranted to betterascertain whether any association exists.The potential effects of BBS/GRP on breast cancers appearbetter established than the effects of gastrin. Breast milkcontains GRP, and receptors for GRP have been noted in amajority of breast cancers (284). A recent report by Reubi et al.(284) found that high-density GRP receptors were detectedin neoplastic mammary cells using in vitro autoradiography:29 of 46 invasive ductal carcinomas, 11 of 17 ductal carcinomasin situ, one of four invasive lobular carcinomas, oneof two lobular carcinomas in situ, and one mucinous and onetubular carcinoma. A heterogeneous GRP receptor distributionwas found in 32 of 52 invasive carcinomas and 12 of 19cases of carcinoma in situ. GRP receptors were also presentin normal breast tissue to some degree and displayed nocorrelation with the amount of receptors found in neoplastictissues. These data suggest that GRP may contribute to bothneoplastic and nonneoplastic breast tissue growth and thepotential of GRP-targeting of breast tissue for scintigraphyand directed chemotherapies. In this regard, a recent reportby Bajo et al. (285) demonstrated the potential utility of specificBBS antagonists on the inhibition of breast cancergrowth. The BBS/GRP inhibitors RC-3095 and RC-3940 IIgiven for 6 wk produced a 40 and 50% reduction in thevolume of MDA-MB-435 human breast cancer cell xenografts,respectively. The mechanism of action may bethrough both direct and indirect effects because BBS wasnoted to decrease the expression of the Her-2/neu oncoproteinand, furthermore, decrease expression of AP-1 transcriptionfactors (c-jun and c-fos). These data suggest that specificBBS/GRP antagonists may be useful as adjuvant therapy forbreast cancer patients in a similar fashion to tamoxifen andHerceptin being commonly used in the treatment regimen.Further work is required to establish which patients maybenefit from BBS/GRP receptor antagonists.2. Lung cancer. Lung cancer is the leading cause of cancerrelateddeaths in the United States. Frequently, lung cancershave spread beyond surgical resection at the time of diagnosis.Therapeutic attempts to limit this disease are thenconfined to adjuvant therapies; therefore, to realize improvementin the mortality from lung cancers, improved chemotherapeuticstrategies are needed.There have been a number of studies linking GRP andBBS-like peptides (BLPs; a group including GRP and neuromedinB) in the regulation of small cell lung cancer (SCLC),suggesting that these BLPs act in an autocrine or paracrinefashion to stimulate growth (286–288). Human BLPs, specificallyGRP, are produced and secreted by SCLC cells, anda number of these cells express the GRP receptor and neuromedin-B-preferringBBS receptor (289). Thomas et al. (286)demonstrated that potent BLP antagonists, BIM 26182 andBIM 26189, inhibited the proliferation of SCLC 41 cells, whichexpress GRP receptor and prepro-GRP. Furthermore, theseBIM compounds inhibited growth of SCLC 41 and SCLC 75tumor growth in vivo. However, these compounds had noeffect on two other SCLC cell lines, SCLC 6 and SCLC 74R,which do not express GLP receptor. Cuttitta et al. (287) notedinhibition of SCLC xenografts in athymic nude mice using anantibody that binds to the C terminal of BLPs (includingGRP). Antibody administration given three times daily for4 wk resulted in a greater than 90% inhibition in tumorgrowth compared with control animals receiving nonspecificantibody. Phase I trials with the C-terminal binding antibody(2A11) reported no toxicity; however, the clinical efficacy hasyet to be established (288).Recent studies (290, 291) have analyzed prepro-GRP expressionas a potential tumor marker to aid in the diagnosisof SCLC and demonstrate sensitivities of only 50–65%. Althoughexpression of prepro-GRP in SCLC cells may be usefulin the determination of the specific diagnosis, it is likelythat other markers, in combination with GRP expression, willprovide more sensitive data. In addition to SCLC, Siegfriedet al. (292) demonstrated that GRP was produced in thebronchiolo-alveolar cancer cell line A549. GRP produced bythese cells was further demonstrated to be trophic for asquamous carcinoma cell line in vitro, suggesting that GRPmay be a potential stimulant of non-small cell lung carcinomaas it has been established for SCLC. These studiesprovide compelling data to suggest that BLPs may play asignificant role as either an autocrine or paracrine agent inSCLC, as well as non-SCLC. Therefore, BLP antagonists orantibodies may provide useful therapy in these patients.NT has been shown also to play a role in lung carcinomas.Most recently, Moody et al. (293) demonstrated that NT waspresent in measurable amounts (0.06–5.1 pmol/mg protein)in half of the classical SCLC cell lines. The effects of NTRantagonist, SR48692, were investigated in the lung cancer celllines NCI-H209 and H345 (294). SR48692 inhibited NTmediatedCa 2 mobilization in NCI-H209 cells and c-fosmRNA induction and proliferation of both cells in a dosedependentfashion. Furthermore, SR48692 inhibited in vivogrowth of NCI-H209 xenografts.3. Prostate cancer. Cancer of the prostate is the most commoncancer in men in the United States and the second leadingDownloaded from edrv.endojournals.org by on July 16, 2007

Thomas et al. • Gastrointestinal Hormones and Proliferation Endocrine Reviews, October 2003, 24(5):571–599 589cause of cancer deaths, accounting for 30% of new cancerdiagnoses in men (288). Prostate cancer progression can belimited with androgen (testosterone) withdrawal; however,there is increasing interest in the effects of other hormoneson this disease.A subset of prostate cancers was noted to be insensitiveto the effects of androgen withdrawal (i.e., the removal oftestosterone failed to promote tumor regression) (295–297).Interestingly, clusters of neuroendocrine cells were oftenfound in this subset of cancers. Sehgal et al. (296) demonstratedthat the androgen-sensitive LNCap human prostatecancer cell line produced and secreted NT after androgenwithdrawal. Furthermore, LNCap cells expressed a functionalNTR and were stimulated to proliferate with exogenousNT administration after withdrawal of androgen. Thesedata suggested that NT stimulates proliferation of prostatecancer cells during conditions of prostate cancer androgeninsensitivity, which provides support for the potential use ofNTR antagonists as potential therapy for a subset of prostatecancers that continue to grow after androgen withdrawal.Seethalakshmi et al. (297) noted similar effects using NT inthe androgen-insensitive PC3 prostate cancer cell line. Recently,Dal Farra et al. (298) noted expression of the NTRsubtype, NTR 3, uniformly in human prostate cancer cells.Transfection of the Chinese hamster ovary cells with NTRrendered these cells sensitive to the growth-promoting effectsof NT. Therefore, extrapolation of these results to prostatecancers suggests that NT, acting through the NTR subtype,NTR 3, may be responsible for promoting growth inprostate cancer cells. Blocking this receptor subtype providesanother potential avenue for the adjuvant treatment of prostatecancers.Evidence suggests that BBS/GRP may affect prostatecancer growth. Pinski et al. (299) tested the effects of thesomatostatin analog, RC-160, and the BBS/GRP antagonist,RC-3095, in Copenhagen rats bearing the anaplastic,androgen-independent Dunning R3327-AT-1 prostatic cancertumors. A significant reduction in tumor volumes andweights was noted with RC-160 (60 g/d for 332 d) as comparedwith control. RC-3095, at 100 g/d, reduced tumorvolume after 7 d, but after 18 d the inhibition was no longerapparent. Although the somatostatin inhibitor appeared tosuppress Dunning R3327-AT-1 cell growth in vivo, in vitrostudies failed to demonstrate a high-affinity receptor forsomatostatin, although the receptor for GRP was detected.Furthermore, only RC-3095 was capable of in vitro inhibitionof R3327-AT-1 cells. These findings indicated that BBS/GRPmay play a more direct role in prostate cancer proliferation.Consistent with these results, Jungwirth et al. (300) demonstratedthat two new BBS/GRP antagonists, RC-3940-II andRC-3950-II, significantly decreased DU-145 xenograft tumorvolume when compared with control.4. Neuroblastomas. Neuroblastoma is the most common extracranialsolid malignancy of childhood and has a mortalityrate exceeding 50%, particularly in older children (301). Theclinical behavior of neuroblastoma is varied and unpredictableand can range from spontaneous tumor regression, maturationfrom a malignant to a benign lesion or progression(302, 303). This unpredictable feature of neuroblastoma suggeststhat malignant transformation of cells may result, inpart, from a failure to respond to normal signals regulatingdifferentiation and proliferation. The GI hormones that havebeen most closely associated with effects on neuroblastomagrowth are somatostatin and GRP.Borgstrom et al. (304) demonstrated that somatostatintreatment inhibited the growth of the somatostatin receptorpositivehuman neuroblastoma cell line SH-SY5Y whenimplanted as xenografts in athymic nude rats. Moreover,Cattaneo et al. (305) demonstrated that the somatostatinanalog lanreotide (BIM 23014) inhibited MAPK activity andplatelet-derived growth factor-induced Ras protein activationin SY5Y neuroblastoma cells. The inhibition of bothMAPK and Ras has been implicated in the inhibition oftumor cell proliferation and provides strong evidence thatsomatostatin and its receptors can regulate neuroblastomagrowth. Most recently, two separate studies have shown thatthe absence of a functional somatostatin receptor, more specificallythe subtype 2, was strongly correlated with a lessfavorable prognosis in patients with neuroblastomas (306,307). Therefore, detection of somatostatin receptors in neuroblastomasmay provide for an assessment of overall prognosis,as well as potentially providing a mechanism for inhibitingneuroblastoma growth in patients with somatostatinreceptor-positive tumors.Recent studies have implicated GRP and its receptor as apotential autocrine or paracrine factor in neuroblastoma cellgrowth. Sebesta et al. (308) assessed 19 resected neuroblastomaspecimens and identified expression of GRP and GRPreceptor mRNA in all 19. Kim et al. (309) assessed the immunostainingpatterns of GRP and GRP receptor in a numberof resected neuroblastoma specimens of varying grade.Immunohistochemical analysis of 33 paraffin-embeddedneuroblastomas from patients demonstrated an increasedexpression of GRP receptor in a higher percentage of undifferentiatedtumors when compared with more benign anddifferentiated tissue. GRP receptor mRNA was detected inthe neuroblastoma cell lines SK-N-SN, IMR-32, SN-SYSY,and LAN-1. Furthermore, GRP treatment was shown to mobilize[Ca 2 ] i in two neuroblastoma cell lines and, more importantly,stimulated growth in all four cell lines. These datademonstrate the synchronous relationship between GRP andGRP receptor in neuroblastomas, with expression of GRPreceptor correlating with more aggressive tumors. Additionally,the demonstration of increased proliferation in neuroblastomacells in vitro after GRP treatment suggests that GRPmay act as an autocrine and/or paracrine growth factor forneuroblastomas.V. Future Perspectives and Therapeutic ImplicationsGI hormones have been used clinically as both diagnosticand therapeutic agents. For example, administration ofCCK-8 can help establish the diagnosis of biliary colic, administrationof secretin has been useful in the diagnosis ofequivocal patients with the Zollinger-Ellison syndrome, andadministration of gastrin has been useful to assess maximalacid output in patients in whom the diagnosis of Zollinger-Ellison syndrome is being considered (310). Somatostatin isDownloaded from edrv.endojournals.org by on July 16, 2007

590 Endocrine Reviews, October 2003, 24(5):571–599 Thomas et al. • Gastrointestinal Hormones and Proliferationthe GI peptide that has been used most extensively. Somatostatinanalogs have been used to decrease pancreatic andGI secretions associated with fistulas (311). In addition,somatostatin therapy provides symptomatic relief fromhormone overproduction secondary to carcinoid tumorsor other endocrine-producing tumors (312). Furthermore,octreotide radionucleotide scans provide useful diagnostictools to identify endocrine tumors (158).GI hormones may have direct clinical applicability to diseasesof the nonneoplastic GI tract and pancreas. Agents thatblock hormone receptors or hormone release may be usefulas a potential adjuvant therapy in patients with GI malignancies.As more specific and longer-acting agents are developed,it is anticipated that the use of GI hormones orantagonists, depending on the clinical scenario, may providenovel therapies for various GI diseases.A. Nonneoplastic GI diseases1. Ulcer healing. The potential utility of GI hormones in certaininflammatory and atrophic diseases of the GI tract has beenpostulated on the basis of experimental animal models. Inpeptic ulcer disease, Schmassmann and Reubi (313) demonstratedincreased ulcer healing rates in the rat stomach usinga potent CCK-B/gastrin receptor antagonist, YF-476, duringthe early phase of ulcer healing (d 0–8), and using G-17 inthe later phases of healing. These results clearly demonstratethe improved wound-healing ability of inhibiting gastrinbinding (during the early phase) and then modulating gastrinlevels (in the later phase) to enhance healing rates forpeptic ulcer disease.2. Gut disuse or atrophy. The potential use of trophic agents hasreceived a considerable amount of attention in diseases of gutdisuse or atrophy. Trophic peptides that can maintain oraugment GI mucosa during periods of gut disuse include NT,BBS/GRP, and GLP-2 (33, 34, 42, 123, 149). In particular, theseagents may be of use in critically ill patients who are unableto take enteral nutrition, a situation that results in a profoundintestinal mucosal atrophy. Moreover, the use of GI hormonesmay be of potential utility in patients with short bowelsyndrome, a condition in which it would be important toincrease the adaptive mucosal hyperplasia so that these patientsare able to survive without long-term parenteral nutrition.Clinical studies have shown a potential advantageusing a combination of glutamine with GH, suggesting thatthis may be a useful therapy for patients with short bowelsyndrome (314). The use of GI hormones would offer morespecific agents to selectively stimulate gut mucosal growth.In this regard, we have shown that NT can augment theadaptive hyperplasia associated with small bowel resectionin rats (136). Consistent with our findings, others have notedsimilar effects of NT on gut growth using various resectionmodels (137, 138, 315). Similar findings have been noted forGLP-2 and, in a limited clinical trial assessing eight patientswith short bowel syndrome, patients were treated withGLP-2 for 35 d, which resulted in improved intestinal energyabsorption, decreased energy excretion, increased bodyweight and lean body mass, decreased fat mass, and enhancedurinary creatinine excretion (316). These results areencouraging but are neither definitive nor mechanisticallyunderstood. Confirmation of these results with a larger prospective,randomized trial is needed before any definitiveconclusions can be made. However, it seems likely that GIhormones, such as GLP-2, NT, or BBS/GRP, alone or incombination, may prove to be useful therapy in patients withdiseases or conditions in which gut mucosal growth wouldbe advantageous.3. Inflammatory conditions. GI hormones may also provide aprotective effect for the GI mucosa during periods of inflammation.For example, some chemotherapeutic agents are associatedwith a severe enterocolitis, which can greatly limitthe use of these drugs. In experimental studies, Chu et al.(124) demonstrated that the administration of BBS greatlyameliorated the effects of MTX on the intestinal mucosa andincreased survival of rats given MTX. GLP-2 has likewisebeen shown to provide a protective effect for the GI mucosaduring episodes of chemotherapy-induced enterocolitis(155). Clinical trials have yet to be performed to assess the useof GI hormones in this setting. However, given the experimentalresults, it appears clear that, in certain settings, administrationof GI hormones can provide a short-term protectiveeffect for the intestinal mucosa.B. GI cancersThe use of agents that block hormone receptors, as well asthe antitrophic hormone somatostatin, have been assessed inlimited clinical trials in cancer patients. In a recent phase I/IItrial by Smith et al. (317), gastrin-17-diphtheria toxoid (G17-DT; Gastrimmune), an immunogen capable of producinghigh-affinity neutralizing antibodies directed against G-17,was assessed in 50 patients with advanced colorectal cancer.Eight percent of patients had measurable antibody formation,and no systemic side effects were noted (317). Theantibody levels were sufficient to compete with G-17 bindingand neutralize postprandial increases in gastrin. One of thecenters in this multicenter trial noted that two patients haddisease stabilization with administration of G17-DT. Thesedata demonstrate that this agent is not toxic to humans andcan produce increased levels of gastrin antibody. However,its potential utility in patients with advanced colorectal cancerremains to be assessed in larger clinical trials. In anotherstudy, Watson et al. (318) assessed the effect of G17-DT in thetreatment of patients with gastric cancers. Limited data fromone center demonstrated tumor stabilization or response ofthe disease to treatment in 80% of the patients treated withG17-DT (318). These studies provide evidence that agentsthat block gastrin may be of potential utility in patients withgastric cancers in whom surgical therapy alone is usually notcurative.In another study, Abbruzzese et al. (319) assessed the effectsof a CCK receptor antagonist, MK-329, in 18 patientswith advanced pancreatic cancer. Unfortunately, this receptorantagonist had no effect on tumor progression or overallsurvival. However, there was no information on the status ofCCK receptors in the tumors of these patients. In addition,these patients had advanced disease in which other therapieshad already been attempted. In a more recent prospective,Downloaded from edrv.endojournals.org by on July 16, 2007

Thomas et al. • Gastrointestinal Hormones and Proliferation Endocrine Reviews, October 2003, 24(5):571–599 591double-blind study assessing loxiglumide, a CCK-A receptorantagonist, in 64 pancreatic cancer patients, no appreciableeffect on survival or tumor size progression was noted (320).Once again, though, the status of CCK receptors in thesecancers was not evaluated. With the production of morespecific and longer acting antagonists, future clinical trialsshould be designed for pancreatic cancer patients with CCKreceptor-positive cancers. In this way, therapy could be betterdesigned to the particular cancer. In addition, the use ofthese receptor antagonists may have more utility combinedwith more conventional therapeutic agents, much as tamoxifenis often used as part of a regimen for breast cancertreatment.Clinical trials have been performed to assess somatostatinin the growth of various endocrine and nonendocrine cancers(321). The results have been equivocal. Somatostatin analogshave been used primarily for symptomatic control in patientswith advanced endocrine tumors, usually with extensiveliver metastases. The reported effects of these analogs ontumor regression have often been based on a small experienceand usually rely on serial computed tomography orliver scan. Interpretation of an antiproliferative effect is furthercomplicated by the use of multiple therapeutic interventions,including chemotherapy and embolization for endocrinetumors. Kraenzlin et al. (322) first reported thatoctreotide produced shrinkage of a hepatic metastasis in apatient with a VIPoma. In a later study with long-term follow-upin four patients with VIPomas, Williams et al. (323)could not demonstrate tumor regression using octreotide.Studying the effects of octreotide in patients with endocrinetumors is further complicated by the fact that these tumorsare relatively rare and tumor growth is usually slow andunpredictable. Therefore, because these tumors are so infrequent,this makes successful evaluation of the role of theseanalogs extraordinarily difficult.Somatostatin analogs have also been assessed for pancreaticand colorectal cancers (279, 324, 325). A preliminary trialfound that octreotide (500 g/d for 6 months) conferredsome survival advantage and improved quality of life in fourpatients with advanced pancreatic cancer (326). In anotherstudy, Goldberg et al. (325) reported in a phase III randomized,double-blind study of 260 patients with colorectal cancerthat octreotide failed to reduce tumor progression andimprove patient survival. With the synthesis of more specificand longer acting analogs, the utility of these agents for solidtumors of the GI tract should be reassessed. In this regard,Szepeshazi et al. (279) recently described a novel compound,AN-238, which contains a cytostatic somatostatin analoglinked to 2-pyrrolinodoxorubicin. This directed therapy resultedin enhanced tumor inhibition of the human colorectalcancer cells HCT-15 and HT29. Taken together, these datashow that somatostatin-targeted therapies may providemore benefit compared with current somatostatin analogs. Inthe future, one can envision tailoring therapy for patientswith GI malignancies on the basis of the receptor status ofthese tumors. For example, patients with GI cancers thatpossess somatostatin receptors may be potential candidatesto receive somatostatin-directed therapy. Alternatively, patientswith GI cancers with CCK, gastrin, or NT receptorsmay be candidates for agents that either block the receptoror inhibit hormone release as a part of an overall cancerchemotherapy regimen.AcknowledgmentsWe thank Liz Cook, Eileen Figueroa, and Karen Martin for manuscriptpreparation.Address all correspondence and requests for reprints to: B. MarkEvers, M.D., Department of Surgery, The University of Texas MedicalBranch, 301 University Boulevard, Galveston, Texas 77555-0536. E-mail:mevers@utmb.eduResults from our laboratories were supported by National Institutesof Health Grants R01-DK58119 (to M.R.H.), P01-DK35608 and R01-DK48345 (to C.M.T.), and R37-AG10885 and T32-DK07639 (to B.M.E.).R.P.T. is the recipient of a Jeane B. Kempner Scholars Award.References1. Edkins JS 1906 The chemical mechanism of gastric secretion.J Physiol 34:1332. Komarov SA 1938 Gastrin. Proc Soc Exp Biol Med 38:5143. Walsh JH 1994 Gastrointestinal hormones. In: Johnson LR, AlpersDH, Christensen J, Jacobson ED, Walsh JH, eds. Physiology of thegastrointestinal tract. 3rd ed. New York: Raven Press; 1–1284. Modlin IM, Tang LH 1993 A new look at an old hormone: gastrin.Trends Endocrinol Metab 4:51–575. Gardner JD, Jensen RT 1990 Roles of receptors in expression ofgastrointestinal hormone function. 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Thomas et al. • Gastrointestinal Hormones and Proliferation Endocrine Reviews, October 2003, 24(5):571–599 599evaluation and safety of loxiglumide (CCK-A receptor antagonist)in nonresectable pancreatic cancer patients. Italian Pancreatic CancerStudy Group. Pancreas 14:222–228321. Hejna M, Schmidinger M, Raderer M 2002 The clinical role ofsomatostatin analogues as antineoplastic agents: much ado aboutnothing? Ann Oncol 13:653–668322. Kraenzlin ME, Ch’ng JL, Wood SM, Carr DH, Bloom SR 1985Long-term treatment of a VIPoma with somatostatin analogue resultingin remission of symptoms and possible shrinkage of metastases.Gastroenterology 88:185–187323. Williams G, Anderson JV, Williams SJ, Bloom SR 1987 Clinicalevaluation of SMS 201-995. Long-term treatment in gut neuroendocrinetumours, efficacy of oral administration, and possible usein non-tumoural inappropriate TSH hypersecretion. Acta EndocrinolSuppl (Copenh) 286:26–36324. Ebert M, Friess H, Beger HG, Buchler MW 1994 Role of octreotidein the treatment of pancreatic cancer. Digestion 55(Suppl 1):48–51325. Goldberg RM, Moertel CG, Wieand HS, Krook JE, Schutt AJ,Veeder MH, Mailliard JA, Dalton RJ 1995 A phase III evaluationof a somatostatin analogue (octreotide) in the treatment ofpatients with asymptomatic advanced colon carcinoma. NorthCentral Cancer Treatment Group and the Mayo Clinic. Cancer76:961–966326. Cirillo F, Bottini A, Brunelli A, Zuffada S, Bassi M, Filippini L,Alquati P 1998 Octreotide in the treatment of advanced pancreatictumor. Preliminary study. Minerva Chir 53:979–9853rd European Congress of Andrology/16th Congress of the German Society of AndrologySeptember 11–14, 2004Münster, GermanyThe 3rd ECA will be the premier event in Andrology in 2004 in Europe, sponsored by the European Academyof Andrology (EAA) and the German Society of Andrology (DGA). It brings together clinicians and basicscientists active in andrology and will cover all aspects of andrology with emphasis on control of spermatogenesis,spermatogonial stem cells, therapeutic use of androgens, erectile dysfunction, male infertility,assisted reproduction, paternally mediated teratogenicity, prostate cancer, testicular tumors, environmentand reproduction, and finally male contraception.Further information, registration and abstract submission through the web site: www.3rd-eca.deFurther contact: Prof. Dr. E. Nieschlag, Institute of Reproductive Medicine of the University, D-48129Muenster, Germany, Tel: 49 0251/83 56096, Fax: 49 0251/8356093, E-mail: nieschl@uni-muenster.deIOF World Congress on OsteoporosisThe International Osteoporosis Foundation is pleased to invite you to participate in the IOF World Congresson Osteoporosis to be held in Rio de Janerio (Brazil), May 14–18, 2004. This event is your chance to hear—andmeet—the leading experts in the field and learn the latest developments in basic research and clinical andtherapeutic advances. Online abstract submission and registration can be found at www.osteofound.orgContact: IOF–Congress Secretariat, 71 cours Albert Thomas, 69447 Lyon, France, Tel: 33472914177,Fax: 33 4 72 36 90 52, E-mail: info@osteofound.orgDownloaded from edrv.endojournals.org by on July 16, 2007

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