e., inflammation FK506 ic50 and ductular reaction,

unpublished observations), the data clearly reveal a direct action of OPN on Collagen-I protein expression, a key event in liver fibrosis. Hence, OPN appears to induce scarring per se. This is, indeed, also supported by the finding that though ALT activity and the necrosis and inflammation scores were similar, there was increased portal, bridging and sinusoidal fibrosis, along with enhanced width of the collagenous septa in CCl4-injected OpnHEP Tg mice, compared to their WT littermates. Notably, OpnHEP Tg mice developed spontaneous fibrosis over time, whereas WT mice did not. Last, in line with the results using OpnHEP Tg mice and the in vitro data, fibrilar Collagen-I content and scar thickness was significantly lowered by OPN ablation in vivo. It is likely that secreted OPN allows paracrine signaling to HSCs, whereas endogenous OPN expression Tanespimycin in HSCs signals in an autocrine fashion, amplifying fibrogenic response. The cell- and matrix-binding ability of OPN may also facilitate a proper stromal and fibrillar collagen network

organization. Overall, it is reasonable to propose that OPN may drive the fibrogenic response, among others, by directly regulating Collagen-I deposition. Thus, OPN emerges as a key soluble cytokine and ECM-bound molecule promoting liver fibrosis. The authors are very grateful to the following investigators: David T. Denhardt (Rutgers University, Newark, NJ) for his generous gift of the 2A1 Ab and for the Opn−/− mice in 129sv background; Satoshi Mochida (Saitama Medical University, Saitama, Japan) for providing the OpnHEP Tg mice; Andrea D. Branch (Mount Sinai School of Medicine, New York, NY) for donating the human liver protein lysates; Toshimitsu Uede (Hokkaido University, Sapporo, Japan) for the Ad-OPN and Ad-LacZ; John Engelhardt (University of Iowa, Iowa City, IA) for the recombinant Ad expressing the NFκB-Luc reporter; and Feng Hong (Mount Sinai School of Medicine) for supplying the primary human HSC isolated from normal liver margin of patients undergoing hepatic tumor resection. The authors are also very thankful to all former

and current members from the Nieto Laboratory MCE for their helpful comments and suggestions throughout this project as well as for their critical review of the manuscript for this article. Special thanks go to Marcos Rojkind, Arthur I. Cederbaum and David T. Denhardt for their constant support and for their very helpful insight throughout the course of this project. Additional Supporting Information could be found in the online version of this article. “
“Pancreatic cancer is one of the major causes of cancer death. Most patients present with advanced disease and only 10–15% of patients can undergo resection. There are numerous molecular alterations that are involved in the pathogenesis of pancreatic cancer, and there are precursor lesions that progress to invasive cancer.