Hepatic metastases represent the dominant form of hematogenous spread of pancreatic cancer and a primary cause of cancer-related death. Animal models developed to dissect the mechanisms surrounding hematogenous metastasis of tumor cells to the liver describe a very inefficient process in which most cells that embolize to hepatic sinusoids via the portal vein do not develop into metastatic tumors. However, these models do not address the potential impact of humoral cytokines produced by a remote primary tumor. Systemic levels of tumor-derived vascular endothelial growth factor (VEGF) are nearly five-times normal in all patients with pancreatic adenocarcinomas, and elevated levels predict cancer-related death. The central hypothesis of this proposal is that tumor-derived VEGF affects changes in host liver sinusoidal endothelial cells (SEC) that ultimately increase the efficiency of hematogenous metastasis development in the liver. To determine the function of tumor-derived VEGF in the metastasis of pancreatic cancer to the liver the following aims will be addressed.
Aim 1. Identify in vivo changes in liver sinusoidal endothelial cells in mice after exposure to systemic recombinant VEGF or tumor-derived VEGF.
Aim 2. Determine the efficiency of early hepatic micrometastasis development in mice with and without blockade of systemic or tumor-derived VEGF. Unique capabilities of this collaborative effort will allow the examination of this hypothesis. First, an orthotopic pancreatic mouse model coupled with sensitive structural and functional imaging capabilities allows for evaluation of temporal changes in the host liver. Second, novel antibodies against tumor-derived VEGF and VEGF-activated endothelial cells have been raised and shown to control the growth of pancreatic tumor xenografts and bind to VEGF-activated blood vessels in pancreatic tumors; these reagents allow identification of VEGF-induced changes. This laboratory effort represents a partnership between two investigators, a physician scientist with clinical and research expertise in metastasis of pancreatic cancer and a research scientist with expertise in vascular biology and tumor angiogenesis, both committed to the study of tumor-host interactions in pancreatic adenocarcinoma.
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