Shining the spotlight on shed KRAS in pancreatic cancer.

The pancreas is a complex organ functionally compartmentalized into exocrine and endocrine units. Acinar cells synthesize digestive pro-enzymes that are secreted into the ductal system, which starts as small pancreatic ductules that subsequently connect into larger and larger ducts to ultimately form the main pancreatic duct. It is via the main pancreatic duct (and occasionally also via an accessory duct) that these secreted products are released into the duodenum and the gastrointestinal tract. Ductal cells not only provide a structural conduit, but also secrete a bicarbonate-rich fluid. The endocrine islets, which are dispersed throughout the exocrine pancreas, produce insulin and other islet hormones. Blood vessels, lymphatics, nerves and sparsely distributed connective tissue constitute the rest of the pancreas. The well-organized architecture of the normal pancreas is dramatically altered in pancreatic ductal adenocarcinoma (PDAC), where there are regions of cancer cells that either form ductal-like structures when the cancer is well differentiated or appear as amorphous and invasive cells when the cancer is poorly differentiated. In addition, PDAC is associated with foci of proliferating ductal cells and degenerating acinar cells, pockets of pancreatic intraepithelial (PanIN) lesions with varying degrees of dysplasia, as well as regions of acinar to ductal metaplasia (ADM) and inflammatory cell infiltrates. Superimposed on these alterations is a dense stroma which results from collagen deposition by proliferating cancer associated fibroblasts and pancreatic stellate cells. PanIN-1A cells have a columnar phenotype, and in some cases abundant supra-nuclear, mucin-containing cytoplasm. PanIN-1B lesions exhibit papillary architecture, whereas PanIN-2 lesions exhibit nuclear abnormalities that are more pronounced in PanIN-3 where there are also occasional mitotic figures, and budding of cells into the lumen.1 Chronic pancreatitis (CP) is also associated with acinar cell atrophy, stroma formation, foci of inflammatory cells and variable regions of ADM in conjunction with an increased propensity for PanIN formation.2-4 These histological similarities may sometimes lead to difficulties in differentiating between CP and PDAC, even after histological evaluation of a pancreatic biopsy. The biological aggressiveness of PDAC derives, in part, from the multiple molecular alterations that are associated with this malignancy. Thus, there is a high frequency (90-95%) of activating KRAS mutations, often occurring in conjunction with mutations in the P16/CDKN2A, TP53 and SMAD4/DPC4 genes, overexpression of tyrosine kinase receptors and their ligands, and suppression of Tumor Growth Factor-beta (TGF-β)-mediated growth constraints.59 The fact that 30-40% of early PanIN lesions bear activating KRAS mutations and that more advanced PanINs exhibit a much higher rate of such mutations (70-85%) have pointed to a pivotal role for KRAS as initiator of pancreatic carcinogenesis.10 This hypothesis has been reinforced by recent studies with mouse models of pancreatic cancer, in which targeted activation of KrasG12D in pancreatic cells using the Cre/LoxP system causes intraepithelial lesions that occa