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

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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
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