Pancreatic ductal adenocarcinoma (PDAC) is a devastatingly lethal disease with an extremely poor prognosis. Although the specific molecular mechanisms that dictate its biological aggressiveness are yet to be elucidated, PDAC is characterized by mutations in oncogenes and tumor suppressor genes, and by the overexpression of mitogenic and angiogenic growth factors, such as vascular endothelial growth factor-A (VEGF-A). In spite of the marked abundance of this potent angiogenic agent in PDAC, this malignancy is not associated with grossly vascular tumors. Furthermore, VEGF-A has been shown to exert mitogenic effects on pancreatic cancer cells in culture, and these cells express variable levels of high affinity receptor-1 (VEGFR-1) and VEGFR-2. These observations raise the possibility that VEGF-A may also exert direct effects on pancreatic cancer cells in vivo. Recently, we determined that neuropilin-1 (Np-1) and -2 (Np-2), transmembrane co-receptors that promote VEGF-A interactions with their high affinity receptors, are overexpressed in the cancer cells in PDAC. Because neuropilins have been implicated in promoting cell survival, in the present proposal we will test the hypothesis that expression of Np- 1 and Np-2 in the cancer cells in PDAC allows for the activation of a VEGF-A-dependent autocrine pathway that promotes cancer growth, survival and metastasis. To test this hypothesis, we will first determine whether pancreatic cancer cells engineered to overexpress Np-1 and Np-2 exhibit increased mitogenic signaling in response to VEGF-A, enhanced invasive potential, or enhanced survival. Conversely, we will assess the consequences of suppressing Np- 1 and Np-2 expression on responsiveness to VEGF-A. Second, we will use a metastatic nude mouse model of PDAC to study the consequences of these manipulations on tumor growth and metastasis, and to determine whether the in vivo growth promoting effects of neuropilins can be blocked by VEGF-A sequestration. Third, we will determine whether there are significant correlations between Np-1 and Np-2 expression and tumor stage and grade, tumor angiogenesis, and duration of post-operative survival. Together, these studies may ultimately yield novel avenues for therapeutic intervention in this deadly disease.
