review of literature on clinical pancreatology - The Pancreapedia

(ECM) are not fully understood. In this study, sub-populations <strong>of</strong> the human pancreaticcancer cell line, MiaPaCa-2 were established which displayed differences in invasion,adhesion, anoikis, anchorage-independent growth and integrin expression. The resultssuggest that altered expression <strong>of</strong> integrins interacting with different extracellular matrixesmay play a significant role in suppressing the aggressive invasive phenotype. Analysis <strong>of</strong>these clonal populations <strong>of</strong> MiaPaCa-2 provides a model for investigations into the invasiveproperties <strong>of</strong> pancreatic carcinoma [383].Interleukin-13 receptorWhereas interleukin-13 receptor alpha2 chain (IL-13Ralpha2) is overexpressed in a variety <strong>of</strong>human solid cancers including pancreatic cancer, it was investigated its significance incancer invasion and metastasis. It was used two pancreatic cancer cell lines, IL-13Ralpha2-negative HPAF-II and IL-13Ralpha2-positive HS766T, and generated IL-13Ralpha2 stablytransfected HPAF-II as well as IL-13Ralpha2 RNA interference knocked-down HS766T cells.Ability <strong>of</strong> invasion and signal transduction was compared between IL-13Ralpha2-negativeand IL-13Ralpha2-positive cells and tumor metastasis was assessed in murine model forhuman pancreatic cancer with orthotopic implantation <strong>of</strong> tumors. IL-13 treatment enhancedcell invasion in IL-13Ralpha2-positive cancer cell lines but not in IL-13Ralpha2-negative celllines. Furthermore, gene transfer <strong>of</strong> IL-13Ralpha2 in negative cell lines enhanced invasion,whereas its silencing downmodulated invasion <strong>of</strong> pancreatic cell lines in a Matrigel invasionassay. In vivo study revealed that IL-13Ralpha2-positive cancer metastasized to lymphnodes, liver, and peritoneum at a significantly higher rate compared with IL-13Ralpha2-negative tumors. The expression <strong>of</strong> IL-13Ralpha2 in metastatic lesions was found to beincreased compared with primary tumors, and mice with IL-13Ralpha2-positive cancerdisplayed cachexia and poor prognosis. Invasion and metastasis also correlated withincreased matrix metalloproteinase protease activity in these cells. Mechanistically, IL-13activated extracellular signal-regulated kinase 1/2 and activator protein-1 nuclear factors inIL-13Ralpha2-positive pancreatic cancer cell lines but not in IL-13Ralpha2-negative cell lines.Taken together, the results show for the first time that IL-13 can signal through IL-13Ralpha2in pancreatic cancer cells and IL-13Ralpha2 may serve as a prognostic biomarker <strong>of</strong> invasionand metastasis in pancreatic cancer [384].K-rasTo investigate the cellular origin(s) <strong>of</strong> pancreatic ductal adenocarcinoma, it was determinedthe effect <strong>of</strong> pancreatic cancer-relevant gene mutations in distinct cell types <strong>of</strong> the adultpancreas. It was shown that a subpopulation <strong>of</strong> Pdx1-expressing cells is susceptible tooncogenic K-Ras-induced transformation without tissue injury, whereas insulin-expressingendocrine cells are completely refractory to transformation under these conditions. However,chronic pancreatic injury can alter their endocrine fate and allow them to serve as the cell <strong>of</strong>origin for exocrine neoplasia. These results suggest that one mechanism by whichinflammation and/or tissue damage can promote neoplasia is by altering the fate <strong>of</strong>differentiated cells that are normally refractory to oncogenic stimulation [385].KRAS is mutated in more than 90 percent <strong>of</strong> pancreatic cancer patients, and oncogenicKRAS contributes to pancreatic cancer tumorigenesis and progression. In one report, usingan oncogenic KRASV12-based pancreatic cancer cell model, it was developed a chemicalgenetic screen to identify small chemical inhibitors that selectively target pancreatic cancercells with gain-<strong>of</strong>-function KRAS mutation. After screening ~3,200 compounds, it wasidentified one compound that showed selective synthetic lethality against the KRASV12transformed human pancreatic ductal epithelial cell over its isogenic parental cell line. Theseselective KRASV12-synthetic lethal compounds may serve as leads for subsequentdevelopment <strong>of</strong> clinically-effective treatments for pancreatic cancer [386].