Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse.

Hingorani SR, Petricoin EF, Maitra A, Rajapakse V, King C, Jacobetz MA, Ross S, Conrads TP, Veenstra TD, Hitt BA, Kawaguchi Y, Johann D, Liotta LA, Crawford HC, Putt ME, Jacks T, Wright CV, Hruban RH, Lowy AM, Tuveson DA
Cancer Cell. 2003 4 (6): 437-50

PMID: 14706336 · DOI:10.1016/s1535-6108(03)00309-x

To evaluate the role of oncogenic RAS mutations in pancreatic tumorigenesis, we directed endogenous expression of KRAS(G12D) to progenitor cells of the mouse pancreas. We find that physiological levels of Kras(G12D) induce ductal lesions that recapitulate the full spectrum of human pancreatic intraepithelial neoplasias (PanINs), putative precursors to invasive pancreatic cancer. The PanINs are highly proliferative, show evidence of histological progression, and activate signaling pathways normally quiescent in ductal epithelium, suggesting potential therapeutic and chemopreventive targets for the cognate human condition. At low frequency, these lesions also progress spontaneously to invasive and metastatic adenocarcinomas, establishing PanINs as definitive precursors to the invasive disease. Finally, mice with PanINs have an identifiable serum proteomic signature, suggesting a means of detecting the preinvasive state in patients.

MeSH Terms (19)

Animals Basic Helix-Loop-Helix Transcription Factors Carcinoma, Pancreatic Ductal Cyclooxygenase 2 Genes, ras Homeodomain Proteins Humans Immunohistochemistry Isoenzymes Matrix Metalloproteinase 7 Membrane Proteins Mice Mutation Neoplasm Metastasis Neoplasm Staging Pancreas Pancreatic Neoplasms Prostaglandin-Endoperoxide Synthases Transcription Factor HES-1

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