Pancreas microenvironment promotes VEGF expression and tumor growth: Novelwindow models for pancreatic tumor angiogenesis and microcirculation

Pancreatic cancer has a poor prognosis, and treatment strategies based on p reclinical research have not succeeded in significantly extending patient s urvival. This failure likely stems from the general lack of information on pancreatic tumor physiology, attributable to the difficulties in developing relevant, orthotopic models that accurately reflect pancreatic cancer in t he clinic. To overcome this limitation, we developed abdominal wall windows suitable for intravital microscopy that allowed us to monitor angiogenesis and microvascular function noninvasively during tumor growth in vivo. We u sed two complementary tumor models in mice: orthotopic (human ductal pancre atic adenocarcinoma, PANC-1, grown in the pancreas), and ectopic (PANC-1 gr own in the abdominal wall). We found that orthotopic PANC-1 tumors grew fas ter than the ectopic tumors and exhibited metastatic spread in the late sta ge similar to advanced pancreatic cancer in the clinic. Orthotopic PANC-1 t umors expressed vascular endothelial growth factor (VEGF)(121) and VEGF(165 ), contained higher levels of tumor cell-derived VEGF protein, and maintain ed vascular density and hyperpermeability during exponential tumor growth. Orthotopic PANC-1 tumors showed lower leukocyte-endothelial interactions in the early stage of growth. In addition, both VEGF(121) and VEGF(165) promo ted the growth of PANC-1 cells in vitro. Finally, Anti-VEGF neutralizing an tibody inhibited angiogenesis and tumor growth of PANC-1 tumors in both sit es. We conclude that the orthotopic pancreas microenvironment enhances VEGF expression, which stimulates growth of PANC-1 tumors (compared with ectopi c tumors). The mechanism is autocrine and/or paracrine and also is involved in the maintenance of blood vessels. This comparative system of orthotopic and ectopic pancreatic cancer will provide the rigorous understanding of p ancreatic tumor pathophysiology needed for development of novel therapeutic strategies.