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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent studies show that nonamidated gastrins (Gly-gastrin and progastrin) stimulate colonic proliferation. However, the role of nonamidated vs. amidated gastrins in colon carcinogenesis has not been defined. We measured intermediate markers of carcinogenesis in transgenic mice overexpressing either progastrin (hGAS) or amidated gastrin (INS-GAS) in response to azoxymethane (AOM). The hGAS mice showed significantly higher numbers of aberrant crypt foci (140-200% increase) compared with that in wild-type (WT) and INS-GAS mice (P < 0.05) after AOM treatment. The bromodeoxyuridine-labeling index of colonic crypts also was significantly elevated in hGAS mice vs. that in WT and INS-GAS mice. The results therefore provide evidence for a mitogenic and cocarcinogenic role of nonamidated gastrins (progastrin), which is apparently not shared by the amidated gastrins. Although nonamidated gastrins are now believed to mediate mitogenic effects via novel receptors, amidated gastrins mediate biological effects via different receptor subtypes, which may explain the difference in the cocarcinogenic potential of nonamidated vs. amidated gastrins. In conclusion, our results provide strong support for a cocarcinogenic role for nonamidated gastrins in colon carcinogenesis.
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PMID:Mice overexpressing progastrin are predisposed for developing aberrant colonic crypt foci in response to AOM. 1071 58

Several gastrointestinal (GI) hormones, such as gastrin, cholecystokinin, and bombesin, have been reported to affect the development of pancreatic cancer. The receptors for these hormones are found in normal and neoplastic pancreatic cells. Activation of these receptors enhances pancreatic carcinogenesis and promotes the growth of established pancreatic carcinoma either in vitro or in vivo. On the other hand, some studies have shown that these GI hormones may have no effect or may play an inhibitory role in the development of pancreatic cancer. The reasons for the apparent discrepancies in the published literature are discussed in this review. In recent years, increasing emphasis has been placed on the effects of GI hormones on cancer invasion and metastasis. As the transition from noninvasion to the invasive state is the crucial event in cancer development, further investigation of the way in which GI hormones affect the invasion and metastasis of pancreatic cancer may be important for the development of new therapeutic approaches with eventual clinical utility.
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PMID:Roles of gastrointestinal hormones in pancreatic cancer. 1098 27

The polypeptide hormone gastrin was identified nearly a hundred years ago and its role in the regulation of acid secretion is well established. Gastrin also acts as a growth factor and is trophic for the normal gastric oxyntic mucosa. This growth promoting action has led to the extensive investigation of its role in carcinogenesis, in particular colorectal neoplasia. The relationship between gastrin and colorectal adenocarcinoma has been subject to controversy, however the findings from several recent studies have resulted in a clearer understanding of the mechanism of action of gastrin in this is common cancer. The majority of colorectal cancers produce their own gastrin, which may act in an autocrine manner. The tumour cells also express gastrin/CCKB receptors (and/or a combination of isoforms) which mediate the proliferative action. This locally produced gastrin gives rise to a small increase in systemic gastrin levels. Autocrine gastrin may also have a role in tumour development, as expression occurs early in the adenoma-carcinoma sequence. In addition, several studies using animal models have shown that systemic hypergastrinaemia promotes the proliferation of both normal and neoplastic colonic epithelium. Hyperproliferative colonic epithelium in the presence of hypergastrinaemia has been recorded in humans and a well-designed epidemiological study has demonstrated an increased incidence of colorectal cancer. Gastrin is a potential therapeutic target in the treatment of colorectal cancer and several approaches have been assessed. Receptor antagonists and antisecretory agents have been demonstrated to be ineffectual. Novel methods of inhibition, including the use of anti-gastrin antibodies, are currently being evaluated.
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PMID:Review article: gastrin and colorectal cancer. 1101 67

Helicobacter pylori, infecting more than 50% of the world population, results in gastritis, usually located in the antral portion of the stomach, accompanied by hypergastrinemia, the key factor in gastric and colorectal carcinogenesis. Excessive mucosal cell proliferation for many years may eventually result in gastric atrophy, cell mutation and transformation of gastric mucosal cells into gastrin-producing cells, which also express gastrin receptors serving to stimulate cell proliferation and tumor growth. These processes may be completed by the expression of cyclooxygenase-2 (COX-2) as an inflammation enzyme to release excessive amounts of PGE(2), leading to further proliferation, reduction in apoptosis, angiogenesis and tumor growth. H. pylori eradication results in complete regression of MALT lymphoma and subsequent normalisation of excessive gastrin release and COX-2 expression. Reduction of gastrin by active immunisation (gastrimmune), blocking of gastrin receptors with specific blockers and suppression of COX-2 might be helpful in inhibiting tumor growth and invasion.
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PMID:Helicobacter pylori infection and gastrin and cyclooxygenase expression in gastric and colorectal malignancies. 1103 48

The dose-dependence of catechol glandular stomach carcinogenesis was investigated in male F344 rats. Groups of 30 male animals were fed catechol at dietary levels of 0 (control). 0.1, 0.2, 0.4, and 0.8% for up to 104 weeks. Five rats of each group were killed at 34 weeks and the remaining animals were sacrificed at the termination, all undergoing histopathological examination. Moderate retardation of body weight increase was observed in the 0.8% group. but no adverse effects were found in terms of survival. Submucosal hyperplasias and adenomas of the pyloric glands developed in the 0.4 and 0.8% groups, only very minor changes being noted in the 0.1 and 0.2% groups at week 34. Incidences of adenocarcinoma development in the pylorus were 4% and 8% in 0.4% and 0.8% groups, respectively, and 0 in the 0.1% and 0.2% groups, at the termination. Adenomas and submucosal hyperplasias were found in nearly all animals fed 0.2% catechol or more, the incidences of those in 0.1% group being 0% and 56%, respectively. Serum gastrin levels were significantly increased in the 0.2, 0.4, and 0.8% groups at 34 weeks, and in all treated groups at the termination, at extents comparable with the induction of proliferative lesions in the pylorus. The results thus demonstrated that dietary levels of 0.4% and 0.8% catechol long-term induce adenocarcinomas in the pyloric glands, while 0.1 and 0.2% cause benign proliferative lesions, all accompanied by increase in serum gastrin levels. As a no-effect level could not be decided in the present study, further investigation of lower doses is needed to determine whether a threshold exists.
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PMID:Dose-dependent induction of glandular stomach preneoplastic and neoplastic lesions in male F344 rats treated with catechol chronically. 1142 85

Mutation of the K-ras gene is thought to be an early and important event in pancreatic carcinogenesis. In order to study the role of this molecular alteration in the transition from the normal to the neoplastic pancreatic cell, bovine pancreatic duct cells were first immortalized by SV40 large T antigen (Ag) complementary (c)DNA transfection and then transfected with a mutated K-ras gene. As did primary duct cells, the immortalized duct cells (more than 100 passages) expressed cytokeratins, carbonic anhydrase type-II, cystic fibrosis transmembrane conductance regulator (CFTR), and multidrug resistance (mdr). They grew as a single layer after transplantation under plastic domes and formed three-dimensional structures resembling ducts when grown on Matrigel. Cell growth was stimulated by insulin, epidermal growth factor (EGF), transforming growth factor (TGF)-alpha, but cells did not respond to gastrin and CCK-8. They did not form colonies in soft agar nor did they form tumors in nude mice. Immortalized cells transfected with mutated K-ras acquired the ability to form tumors after orthotopic injection into the nude mouse pancreas. It is concluded that SV 40 immortalized bovine pancreatic
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PMID:Immortalized bovine pancreatic duct cells become tumorigenic after transfection with mutant k-ras. 1146 90

Evidence is accumulating that gastrin precursors may act as growth factors for the colonic mucosa in vivo and for colorectal carcinoma cell lines in vitro. The effect of short term administration of synthetic gastrins on the colonic mucosa in vivo, however, has not been reported. The aim of our study was to determine whether continuous systemic infusion of glycine-extended gastrin(17) stimulated proliferation and accelerated carcinogenesis in the colorectal mucosa. A significant increase in colonic mucosal proliferation as assessed by metaphase index was seen in the caecum (23%, p < 0.02) and distal colon (27%, p < 0.001), but not the rectum, after treatment of intact rats with glycine-extended gastrin(17) for 1 week using implanted miniosmotic pumps. Defunctioning of the rectum reduced both the proliferative index and crypt height of the rectal mucosa of untreated rats. Treatment of rectally defunctioned animals with glycine-extended gastrin(17) for either 1 or 4 weeks resulted in a significant increase in both the proliferative index (40% and 93%, respectively) and crypt height (11% and 19%, respectively) of the rectal mucosa. The total number of aberrant crypt foci in intact rats treated with the procarcinogen azoxymethane plus glycine-extended gastrin(17) was increased by 48% compared to the value in controls treated with azoxymethane only (p = 0.01). We conclude that short term administration of glycine-extended gastrin(17) to mature rats not only has a proliferative effect upon colonic mucosa, but also increases the number of aberrant crypt foci formed in the colorectal mucosa after treatment with azoxymethane. Glycine-extended gastrin(17) could thus potentially act as a promoter of carcinogenesis.
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PMID:Short term infusion of glycine-extended gastrin(17) stimulates both proliferation and formation of aberrant crypt foci in rat colonic mucosa. 1174 7

AIM:To investigate the changes of gastric mucosal ascorbic acid secretion in patients with nonulcer dyspepsia and the effect of gastrin on it, and to relate any observed changes to H.pylori infection and mucosal histology.METHODS:Ascorbic acid secretions in patients were examined by collecting continuously gastric juice for one hour after having aspirated and discarded fasting gastric juice. Using the clearance rate (mL/min) of ascorbic acid from blood to gastric juice represented ascorbic acid secretion in the gastric mucosa.Ascorbic acid concentrations in plasma and juice were measured by ferric reduced method.RESULTS:Gastric ascorbic acid secretions in H.pylori-positive patients (1.46mL/min,range 0.27-3.78) did not significantly differ from those in H.pylori-negative patients(1.25mL/min, 0.47-3.14)(P>0.05). There were no significant differences in ascorbic acid secretions between patients with mild (1.56mL/min, 0.50-3.30), moderate (1.34mL/min, 0.27-2.93) and severe (1.36mL/min, 0.47-3.78) inflammation (P >0.05). There were no significant differences in ascorbic acid secretions between patients without activity (1.45mL/min, 0.27-3.14) and with mild (1.32mL/min, 0.61-2.93), moderate (1.49mL/min, 0.50-3.78) and severe (1.43mL/min, 0.51-3.26) activity of chronic gastritis either (P>0.05). Ascorbic acid secretions in patients with severe atrophy (0.56mL/min, 0.27-1.20) were markedly lower than those in patients without atrophy (1.51mL/min, 0.59-3.30) and with mild (1.43mL/min, 0.53-3.78) and moderate (1.31mL/min,0.47-3.16)atrophy(P<0.005). There was a significant negative correlation between ascorbic acid secretion and severity of atrophy (correlation coefficient =-0.43, P<0.005). After administration of pentagastrin, ascorbic acid secretions were markedly elevated (from 1.39mL/min, 0.36-2.96 to 3.53mL/min, 0.84-5.91) (P <0.001).CONCLUSION:Ascorbic acid secretion in gastric mucosa is not affected by H.pylori infection. Gastric ascorbic acid secretion is markedly related to the severity of atrophy, whereas not related to the severity of inflammation and activity. Gastrin may stimulate gastric ascorbic acid secretion. A decreased ascorbic acid secretion may be an important factor in the link between atrophic gastritis and gastric carcinogenesis.
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PMID:Ascorbic acid secretion in the human stomach and the effect of gastrin. 1181 78

An important role for beta-catenin pathways in colorectal carcinogenesis was first suggested by the protein's association with adenomatous polyposis coli (APC) protein, and by evidence of dysregulation of beta-catenin protein expression at all stages of the adenoma-carcinoma sequence. Recent studies have, however, shown that yet more components of colorectal carcinogenesis are linked to beta-catenin pathways. Pro-oncogenic factors that also release beta-catenin from the adherens complex and/or encourage translocation to the nucleus include ras, epidermal growth factor (EGF), c-erbB-2, PKC-betaII, MUC1, and PPAR-gamma, whereas anti-oncogenic factors that also inhibit nuclear beta-catenin signaling include transforming growth factor (TGF)-beta, retinoic acid, and vitamin D. Association of nuclear beta-catenin with the T cell factor (TCF)/lymphoid enhancer factor (LEF) family of transcription factors promotes the expression of several compounds that have important roles in the development and progression of colorectal carcinoma, namely: c-myc, cyclin D1, gastrin, cyclooxygenase (COX)-2, matrix metalloproteinase (MMP)-7, urokinase-type plasminogen activator receptor (aPAR), CD44 proteins, and P-glycoprotein. Finally, genetic aberrations of several components of the beta-catenin pathways, eg, Frizzled (Frz), AXIN, and TCF-4, may potentially contribute to colorectal carcinogenesis. In discussing the above interactions, this review demonstrates that beta-catenin represents a key molecule in the development of colorectal carcinoma.
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PMID:Beta-catenin--a linchpin in colorectal carcinogenesis? 1183 57

Gastrointestinal tumors with DNA mismatch repair (MMR) defects show microsatellite instability (MSI) and harbor frameshift mutations in coding mononucleotide repeats of cancer-related genes (targets). We assessed MSI status in 233 sporadic gastrointestinal tumors. We classified as MSI-H (high-frequency microsatellite instability) 15 (10%) of 150 colorectal cancers and 13 (16%) of 83 gastric cancers. We searched for frameshift mutations in a coding poly(T)(8) tract within the gastrin receptor gene (hGARE), which has a potential role in gastrointestinal carcinogenesis. To this purpose, we screened 43 unstable tumors (including 15 hereditary nonpolyposis colorectal cancer cases previously classified as MSI-H), 98 stable tumors, as well as 3 MMR-deficient and 4 MMR-proficient gastrointestinal cancer cell lines. We found mutations in 8 (19%) of the 43 MSI-H tumors but in none of the 98 stable cancers. hGARE mutation frequency was similar in gastric (23%) and colorectal cancers, including sporadic (13%) and hereditary (20%) cases. All mutated tumors proved to harbor frameshift mutations in other cancer-related genes that are considered as targets in MSI tumorigenesis. The MMR-deficient and gastrin-sensitive LoVo colorectal cancer cells also showed a hGARE heterozygous frameshift mutation, but expressed only the mutated allele. All detected mutations can be predicted to generate a truncated protein carrying amino acid changes. On the basis of genetic findings, we propose hGARE as a new candidate target gene in MSI tumorigenesis. Functional studies are warranted to elucidate the mechanism by which the hGARE mutation might contribute to gastrointestinal carcinogenesis.
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PMID:Frameshift mutations of human gastrin receptor gene (hGARE) in gastrointestinal cancers with microsatellite instability. 1189 5


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