Abstract
Pancreatic cancer cells exclusively harbor the gain-of-function mutation of KRAS. A small subset of cells without the mutation of KRAS harbor the activating mutation of BRAF. This evidence suggests that the RAS-MAPK pathway plays an essential role in the development and progression of pancreatic cancer. Pancreatic cancer may develop through pancreatic intraepithelial neoplasia (PanIN). The activation of KRAS has been already observed in low-grade PanIN, which suggests that the activation is associated with an initiation of the PanIN. The progression of PanIN from low-grade to high-grade may be associated with the inactivation of multiple tumor suppressors including CDKN2A, TP53 and SMAD4. DUSP6 may be associated with the progression from high-grade PanIN to invasive ductal adenocarcinoma. Genetically engineered mouse models (GEM) have been developed to recapitulate the molecular events associated with the progression through PanIN to invasive ductal adenocarcinoma. One of the GEM conditionally expressing activated Kras developed the mouse PanIN and invasive ductal adenocarcinoma, which may well reflect human pancreatic carcinogenesis. PanINs are significantly more common in familial pancreatic cancer cases. RAS-MAPK pathway plays essential roles in pancreatic carcinogenesis. Investigation of downstream targets of MAPK may provide key molecules for malignant phenotypes of pancreatic cancer.
