[Molecular pathways of pancreatic carcinogenesis].
Pancreatic carcinogenesis is still not well characterized and no specific carcinogen has been isolated in humans. Pancreatic adenocarcinoma acquires genetic abnormalities with successive modification of genes involved in the regulation of cell proliferation and differentiation. The kinetic of genetic alterations in pancreatic cancer is not totally elucidated but experimental pancreatic cancer induced by BOP in Syrian golden hamster attempts to approach this problematic. The activating mutation of the K-ras oncogene on codon 12 seems to occur early in pancreatic carcinogenesis regarding the detection of this mutation in preneoplastic dysplastic lesions and tumors such as intraductal mucinous papillary tumors. Tumor suppressor genes are also inactivated leading commonly to the loss of an inhibitory function on cell proliferation. This inactivation occurs with gene mutation, deletion or methylation on one chromosome arm associated with a loss of heterozygosity: it concerns p53, p16/MTS-1, DPC-4/SMAD4. We recently characterized the somatostatin receptor SST2 gene as a potential suppressor gene for pancreatic carcinoma. The kinetic of these gene alterations is unknown in human. At a late stage of tumor development, an increase of telomerase activity, an over expression of growth factors and/or their receptors (EGF, NGF, gastrin, bombesin), of proangiogenic factors (VEGF, FGF, PDGF), of invasiveness factors (metalloproteinases, E-cadherin, urokinase and tissue plasminogen activators) occur. All these molecular events contribute to the progression and to the metastatic potential of this carcinoma. Recently, the identification of human genome and the large scale analysis of transcriptoma will certainly authorize a better knowledge of pancreatic carcinogenesis as well as the identification of new genetic alterations and new clinical markers.
Torrisani
Jérôme
J
INSERM U531 et Service de Gastro-entérologie et Nutrition, CHU Rangueil, 1, avenue J.-Poulhes, 31403 Toulouse Cedex 4, France.
Buscail
Louis
L
D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology; D000818:Animals; D002273:Carcinogens; D002454:Cell Differentiation; D002455:Cell Division; D003062:Codon / Q000235:genetics; D006224:Cricetinae; D011905:Genes, ras; D006801:Humans; D008647:Mesocricetus; D009154:Mutation; D009602:Nitrosamines; D010190:Pancreatic Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology
D002273:Carcinogens; D003062:Codon; D009602:Nitrosamines; C013622:nitrosobis(2-oxopropyl)amine