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

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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
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