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

The epidemiological patterns for pancreatic and biliary cancers reveal more differences than similarities. Pancreatic carcinoma is common in western countries, although 2 Polynesian groups (New Zealand Maoris and native Hawaiians) have the highest rates internationally. In the United States the disease is rising in frequency, predominating in males and in blacks. The rates are elevated in urban areas, but geographic analysis uncovered no clustering of contiguous counties except in southern Louisiana. The origin of pancreatic cancer is obsure, but a twofold increased risk has been documented for cigarette smokers and diabetic patients. Alcohol, occupational agents, and dietary fat have been suspected, but not proven to be risk factors. Except for the rare hereditary form of pancreatitis, there are few clues to genetic predisposition. In contrast, the reported incidence of biliary tract cancer is highest in Latin American populations and American Indians. The tumor predominates in females around the world, except for Chinese and Japanese who show a male excess. In the United States the rates are higher in whites than blacks, and clusters of high-risk counties have been found in the north central region, the southwest, and Appalachia. The distribution of biliary tumors parallels that of cholesterol gallstones, the major risk factor for biliary cancer. Insights into biliary carcinogenesis depend upon clarification of lithogenic influences, such as pregnancy, obesity, and hyperlipoproteinemia, exogenous estrogens, familial tendencies, and ethnic-geographic factors that may reflect dietary habits. Noncalculous risk factors for biliary cancer include ulcerative colitis, clonorchiasis, Gardner's syndrome, and probably certain industrial exposures. Within the biliary tract, tumors of the gallbladder and bile duct show epidemiological distinctions. In contrast to gallbladder cancer, bile duct neoplasms predominate in males; they are less often associated with stones and more often with other risk factors. In some respects, bile duct and pancreatic tumors are alike. The male predominance of both tumors, an association between cholecystectomy and pancreatic cancer, and other considerations have prompted the notion that the same biliary carcinogens may affect the bile duct, ampulla of Vater, or, by reflux, the pancreatic duct. Various epidemiological and interdisciplinary approaches are needed to further clarify the origins of biliary tract and pancreatic cancers, but nutritional studies hold special promise in laying the groundwork for prevention of these tumors.
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PMID:Cancers of the pancreas and biliary tract: epidemiological considerations. 110 53

It is well known that the patients with anomalous arrangement of pancreatobiliary duct (AAPBD) are combined with biliary tract cancer. To clarify possible carcinogenesis of the gallbladder with AAPBD, DNA analysis of the gallbladder epithelium was performed in control (9 cases), AAPBD (26), gallbladder cancer confined in mucosa (10) and noncancerous epithelium around the gallbladder cancer (21). The mean values of DNA score, as already reported by us as an indicator of cell kinetics, were 12.1 (control), 27.2 (AAPBD, Type a), 13.3 (AAPBD, Type b), 14.8 (noncancerous epithelium around cancer) and 77.2 (gallbladder cancer confined in mucosa). The values of DNA score in the epithelium of AAPBD (Type a) showed significantly high level, which was next to that of cancer. Type a AAPBD may be supposed to have potential malignancy because of its accelerated cell cycle. But as Type b AAPBD without accelerated cell cycle combines cancer at least as often as Type a, further studies should be performed to reveal the relationship between cell cycle and malignancy.
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PMID:[Cell kinetic studies on the gallbladder epithelium in patient with anomalous arrangement of pancreatobiliary duct]. 185 2

If peptic ulcer surgery favors the formation of carcinogenic N-nitroso compounds in the gastric remnant, an increased risk of cancer at sites in the gastrointestinal tract distant from the stomach might be predicted. To estimate the risk of carcinomas in the digestive tract, other than the stomach, occurring after partial gastrectomy, we analyzed an Amsterdam cohort of 2,633 post-gastrectomy patients operated on for benign disease between 1931 and 1960. Mortality in the study population was compared with the general Dutch population through person-year analysis. An excess mortality of biliary tract cancer (O/E:2.64; CL:1.32-4.72; p less than 0.01) and pancreatic cancer (O/E:1.65; CL:1.06-2.44; p less than 0.05) was found in males more than 5 years after surgery; females showed only an increased risk of pancreatic cancer in the first 5 years postoperatively (O/E:15.33; CL:1.85-55.43; p less than 0.01), probably due to misdiagnosis. All other non-gastric sites of the digestive tract carried no increased risk for cancer. In males, mortality due to colorectal cancer more than 5 years post-operatively was significantly decreased (O/E:0.58; CL 0.34-0.92; p less than 0.01). The excess mortality of biliary-tract and pancreatic cancer in males, which increases with the duration of post-operative interval, is consistent with a dose-response phenomenon. This study therefore supports the hypothesis that carcinogens are not only locally activated in the gastric remnant, but are hepatically excreted and initiate cancer in the biliary tree and pancreatic duct. Further exploration of this mechanism of carcinogenesis is warranted, since it may also explain the pathogenesis of pancreatic and biliary cancers in patients without gastrectomy.
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PMID:Occurrence of non-gastric cancer in the digestive tract after remote partial gastrectomy: analysis of an Amsterdam cohort. 222 7

Congenital biliary dilatation is frequently complicated by biliary tract cancer, and anomalous junction of the pancreaticobiliary ductal system, a major factor constituting the pathology of this disease, is considered to be important as a background for carcinogenesis in the biliary tract. To clarify the mechanism of carcinogenesis in the biliary tract under the circumstance of anomalous junction, we evaluated the mutagenicity of the contents of the biliary tract in patients with congenital biliary dilatation and analyzed the nuclear atypia of the biliary epithelium by fluorocytometry. A mutagenicity test using Bacillus subtilis showed positive results in 6 of 12 patients. Since mutagenicity correlates well with carcinogenicity, these results suggest the necessity of separation surgery between the bile and pancreatic ducts in patients with anomalous junction regardless of the presence or absence of biliary dilatation. On the other hand, DNA histograms of the nuclei of gallbladder epithelial cells produced by fluorocytometry in 4 patients revealed a high incidence of polyploid DNA in 2 patients with marked hypertrophic changes. These patients were also positive for mutagenicity of the contents of the biliary tract, suggesting that mutagens are involved in the atypia at the cellular and nuclear levels.
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PMID:Pathology of anomalous junction of the pancreaticobiliary ductal system: mutagenicity of the contents of the biliary tract and nuclear atypia of the biliary epithelium. 277 60

p16Ink4 and p15Ink4B are cyclin-dependent kinase 4 inhibitors and link to the regulation of cell cycle in mammalian cells. The genes encoding these inhibitors are located at 9p21, which is a frequent site of allelic loss in various types of tumors. Twenty-five primary biliary tract cancers were examined for somatic mutations in p16Ink4/CDKN2, p15Ink4B/MTS2, p53, and K-ras genes and allelic loss of 9p21 by microsatellite analysis. Four biliary tract cancer cell lines were analyzed for homozygous deletions and point mutations. We found frequent homozygous deletions in p16Ink4/CDKN2 and p15Ink4B/MTS2 genes in the biliary tract cancer cell lines. Each cancer cell line had alteration of either p16Ink4/CDKN2, p15Ink4B/MTS2, or p53 genes. In primary tumors, 16 of 25 (64%) biliary tract cancers had point mutations in the p16Ink4/CDKN2 gene. These include 14 missense and 2 silent mutations. The frequency of mutations in gall bladder cancer and hilar bile duct cancer were 80% (8 of 10) and 63% (5 of 8), respectively. Each of codons 1, 80, and 111 was changed in two cases of these cancers. One of three intrahepatic bile duct cancers, one of two common bile duct cancers, and one of two ampullary cancers had mutations in the p16Ink4/CDKN2 gene. In contrast, no mutation in the p15Ink4B/MTS2 gene, one base change in the K-ras gene, and one loss of heterozygosity at the IFN alpha locus in 25 cancers and one base change in the p53 gene in 19 cancers were observed. These results suggest that p16Ink4/CDKN2, rather than p15Ink4B/MTS2 or p53 genes, and its inactivation may be important in biliary tract carcinogenesis.
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PMID:Mutations of p16Ink4/CDKN2 and p15Ink4B/MTS2 genes in biliary tract cancers. 779

The incidence of carcinoma arising in the wall of a congenital bile duct cyst is high and there is no doubt that these lesions represent a precancerous state of the biliary tract. In almost all cases congenital bile duct cysts are related to anomalous arrangements of the pancreaticobiliary duct system which seems to play a crucial role in the development of cystic bile ducts and biliary carcinogenesis. Bile stasis together with reflux of pancreatic juice causing longstanding inflammation and activation of bile acids might be the factors in carcinogenesis of the exposed bile duct epithelium in the cystic wall. In the case of primary or secondary extrahepatic bile duct cysts, primary excision is mandatory because of the high risk to develop biliary cancer with even nowadays poor prognosis despite advantages in biliary surgery during the last years. We report a case of a young woman in which bile duct cancer was found arising in the wall of a congenital bile duct cyst. Despite radical surgery the outcome was poor proving the high malignant potential of bile duct cancer. The question of possible tumor seeding in hepatobiliary surgery is discussed as a way of inducing hepatobiliary metastatic tumors.
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PMID:Congenital bile duct cyst: a premalignant lesion of the biliary tract associated with adenocarcinoma--a case report. 876 28

Biliary cancer develops in 20-30% of the patients with choledochal cyst and pancreatobiliary malunion. Some bile acid fractions and refluxed pancreatic enxymes into the bile duct is probably responsible for carcinogenesis. Cancer often develops in the extrahepatic bile duct and gallbladder, and rarely in the intrahepatic duct. In cystic dilatation, cancer often occurs in the common bile duct, while in diffuse or non-dilated type it occurs in the gallbladder. Cancer usually occurs in younger patients than does biliary cancer in general population, and the average age is in the 40s. The risk of malignancy in cysts with internal drainage is higher than that in primary cysts, and early removal of the retained cyst should be performed as quickly as possible. Although the prognosis of biliary cancer is usually dismal, aggressive procedures are recently gaining better results than that by conventional methods. The prevention of cancer is the procedure of choice by early excision. Removal of the whole extrahepatic bile duct is necessary, even in case of malunion with no biliary dilatation. Cancer rarely arises in the intrahepatic duct after excisional surgery, due to long standing biliary stricture. Wide anastomosis with ductoplasty should be essential. Cancer also occurs in the remnant duct. Excision of the distal duct in the pancreas is also necessary.
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PMID:[Cancer arising in choledochal cyst and management]. 890 7

Peutz-Jeghers syndrome (PJS) is an autosomal-dominant disorder characterized by hamartomatous polyps in the gastrointestinal tract and by pigmented macules of the lips, buccal mucosa, and digits. Less appreciated is the fact that PJS also predisposes patients to an increased risk of gastrointestinal cancer, and pancreatic cancer has been reported in many PJS patients. It was recently shown that germline mutations of the STK11/LKB1 gene are responsible for PJS. We investigated the role of STK11/LKB1 in the development of pancreatic and biliary cancer in patients with and without the PJS. In a PJS patient having a germline splice site mutation in the STK11/LKB1 gene, sequencing analysis of an intestinal polyp and pancreatic cancer from this patient revealed loss of the wild-type allele of the STK11/LKB1 gene in the cancer. Inactivation of STK11/LKB1, by homozygous deletions or somatic sequence mutations coupled with loss of heterozygosity, was also demonstrated in 4-6% of 127 sporadic pancreatic and biliary adenocarcinomas. Our results demonstrate that germline and somatic genetic alterations of the STK11/LKB1 gene may play a causal role in carcinogenesis and that the same gene contributes to the development of both sporadic and familial forms of cancer.
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PMID:Germline and somatic mutations of the STK11/LKB1 Peutz-Jeghers gene in pancreatic and biliary cancers. 1036 9

Carcinomas of the biliary tract are rare cancers developing from the epithelial or blast-like cells lining the bile ducts. A variety of known predisposing factors and recent experimental models of biliary carcinogenesis (e.g., infection with the liver fluke Opisthorchis viverrini, models of chemically induced carcinogenesis and experimental models of pancreaticobiliary maljunction) have elucidated different stages of this complex system of biliary tumorigenesis. Chronic inflammatory processes, generation of active oxygen radicals, altered cellular detoxification mechanisms, activation of oncogenes, functional loss of tumor-suppressor genes and dysregulation of cell proliferation and cell apoptotic mechanisms have been identified as important contributors in the development of cholangiocarcinomas. In this review, the known mechanisms involved in the carcinogenesis of biliary epithelium are addressed. We will divide the topic into four stages: 1) Predisposition and risk factors of biliary cancer. 2) Genotoxic events and alterations leading to specific DNA damage and mutation patterns. 3) Dysregulation of DNA repair mechanisms and apoptosis, permitting survival of mutated cells and 4) Morphological evolution from premalignant biliary lesions to cholangiocarcinoma. Finally, established and hypothetical future therapeutic strategies directed towards specific pathogenetic events during biliary carcinogenesis will be addressed.
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PMID:Mechanisms of biliary carcinogenesis: a pathogenetic multi-stage cascade towards cholangiocarcinoma. 1043 2

Furan cholangiocarcinogenesis in rat liver is proving to be a unique and useful animal model for investigating important aspects of the cellular and molecular pathogenesis of cholangiocarcinoma potentially relevant to the human disease. We now describe the first culture model of rat cholangiocarcinoma cells derived from a transplantable cholangiocarcinoma originally induced in the liver of a furan-treated rat. An epithelial cell isolate highly enriched in viable cholangiocarcinoma cells was consistently obtained from transplantable cholangiocarcinoma tissue utilizing a similar procedure to that recently developed by us to establish a new rat hyperplastic bile ductular epithelial cell culture model characterized by the appearance of polarized bile ducts in vitro. Primary cholangiocarcinoma cell cultures could be readily established with these isolated cells and, in addition, we established from one such culture a novel rat cholangiocarcinoma cell line designated C611B. Cultured C611B cholangiocarcinoma cells retained a number of important characteristic features of the carcinoma cells of the parent tumor, including marked expression of the tyrosine kinase growth factor receptor proteins c-Met and c-Neu. Under basal culture conditions, the C611B cell line exhibited a cell doubling time of approximately 24 h and was aneuploid, with a predominant chromosomal count of 43. Moreover, C611B cells on collagen gels were 100% tumorigenic when transplanted into inguinal fat pads of syngeneic rats. All tumors formed at the transplantation site were cytokeratin 19-positive, mucin-producing tubular adenocarcinomas whose histological and phenotypic features closely resembled those of the furan-induced parent transplantable rat cholangiocarcinoma. Based on our findings, we believe that this novel rat cholangiocarcinoma cell culture model can serve as a valuable resource for investigating aberrant growth properties and tumor progression in biliary cancer.
Carcinogenesis 1999 Dec
PMID:Establishment of a novel rat cholangiocarcinoma cell culture model. 1059 Feb 29


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