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- W2968800230 abstract "LB-80 Physiologic expression of oncogenic Kras initiates pancreatic tumorigenesis, while subsequent genetic events define the clinical and histopathologic features of the resultant disease. Distinct histopathologic routes to infiltrating pancreatic ductal adenocarcinoma (PDA) have been described with profoundly different prognoses for patients despite possessing overlapping mutational spectra. Invasive disease can arise from pancreatic intraepithelial neoplasias (PanINs), the most common pancreatic precursor lesion, as well as from two distinct classes of cystic neoplasia, intraductal papillary mucinous neoplasms (IPMNs) and mucinous cystic neoplasms (MCNs). We show here that concomitant expression of KrasG12D and haploinsufficiency of the Smad4/Dpc4 tumor suppressor gene results in the development of MCNs. These MCNs arise primarily in the body and tail of the organ and manifest an “ovarian-type” stroma, consisting of focally dense collections of PR-positive and ER-positive cells. The murine MCNs progress through discrete histologic stages, accompanied by LOH of Dpc4 and mutation of either p53 or p16, and culminate in invasive adenocarcinomas, faithfully recapitulating the human disease. This phenotype contrasts dramatically with engineered mutation of either the Trp53 or p16/Ink4a pathways in the setting of targeted KrasG12D expression, in which murine PanINs progress to invasive PDA with distinct biological sequelae. Thus, our findings elucidate an MCN-to-PDA progression scheme analogous to, but distinct from, the classical PanIN-to-PDA sequence and may help explain the dramatically different prognoses for these two pathways to invasive disease. In primary pancreatic carcinoma cell lines with mutation of Trp53 but intact Smad4, TGFβ induces dramatic epithelial-to-mesenchymal transition (EMT) and stimulates cellular migration. Conversely, primary cells from invasive MCNs lacking Smad4/Dpc4 were resistant to these effects, which may also help explain the lower frequency of metastatic lesions and improved survival seen in this setting. That the same overall mutational spectra are encountered in both of these distinct phenotypic routes to invasive adenocarcinoma of the pancreas also suggests that the sequence, as well as the context, in which these critical mutations are acquired helps determine the ensuing pathology." @default.
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- W2968800230 date "2007-05-01" @default.
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- W2968800230 title "Oncogenic KrasG12D and Smad4/Dpc4 haploinsufficiency cooperate to induce mucinous cystic neoplasms and invasive adenocarcinoma of the pancreas" @default.
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