Angiogenesis, the growth of new blood vessels from pre-existing vessels, contributes significantly to cancer progression and metastasis, as the "angiogenic switch" represents a fundamental step in the progression of a solid tumor to a faster growing and more malignant state. Unlike normal vessels, tumor-associated blood vessels are notoriously leaky and tortuous, contributing to their poor function. Accordingly, recent attempts to normalize tumor blood vessels have proven successful as a means for improved delivery of anti-cancer agents. We hypothesize, that by normalizing the tumor vasculature, it should be possible to reduce tumor cell metastasis by limiting tumor intravasation. During tumor angiogenesis, vascular endothelial growth factor (VEGF) and other angiogenic growth factors stimulate endothelial cells to sprout and form new vessels. Simultaneously, vascular smooth muscle cells stimulated by platelet-derived growth factor-BB (PDGF-BB) and its receptor PDGFR2 are recruited to tumor associated vascular sprouts facilitating vessel maturation. We have recently made the observation that the presence of VEGF can block PDGF-dependent regulation of neovascularization and vessel normalization. Thus, by blocking VEGF or the VEGF receptor 2 we can induce increase tumor vessel maturation. It is our hypothesis that VEGF, through its capacity to negatively regulate PDGFR2 function on pericytes, not only has a profound influence on neovascularization and growth of primary tumors, but also significantly impacts tumor cell intravasation, an initial step in the metastatic cascade. A major goal of our proposed studies will be to characterize the composition of the PDGFR2/VEGFR2 complex on tumor vessel associated pericytes and investigate how it regulates the cell migration and proliferation in vitro (Aim 1). We will carefully examine the mechanism by which VEGF suppresses PDGF function impacting blood vessel integrity and pericyte coverage in real time during angiogenesis in mice (Aim 2). Finally, we will determine how differential expression of VEGF/PDGF by tumor cells determines vascular maturation and angiogenesis, and assess how regulation of VEGF expression impacts the progression and metastatic properties of orthotopic and spontaneous pancreatic cancer in mice (Aim 3). Based on these studies we propose a novel therapeutic strategy to control tumor progression and metastasis.
Angiogenesis is the process by which new blood vessels are formed by sprouting from the existing vasculature. We have identified a surprising balance between pro-angiogenic factors which results in the blockade of angiogenesis. A thorough understanding of this system is required for the design of new therapies to manipulate the angiogenic response in order to limit tumor growth, facilitate efficient drug delivery, and ultimately improve outcome for patients suffering from metastatic disease.
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