PROSTATIC VASCULOGENIC MIMICRY: A NEW METASTATIC PATHWAY

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Our laboratory has described a new phenomenon, tumor Vasculogenesis, whereby tumor cells themselves (in the absence of endothelial cells), form vascular channels and tubular networks which facilitate tumor perfusion independent of classical angiogenesis. Preliminary studies utilizing prostate tumors and neoplastic prostate cell lines strongly support the concept that "vasculogenic mimicry" is also exhibited by aggressive prostatic neoplasms. The overall objective of this proposed research, therefore, is to determine the key molecular mechanisms underlying this phenomenon in tumors of the prostate. Specific Aim 1: Characterize the cellular and molecular phenotype of the aggressive prostate cancer cells undergoing vasculogenic mimicry. Hypothesis: Invasive and metastatic prostate cancer cells (but not normal prostate epithelium) undergo vasculogenic mimicry and form vascular channels and tubular networks, which can perfuse the tumor independent of or supplemental to angiogenesis. Specific Aim 2: Examine the molecular interactions between the epithelial and fibroblast-like subpopulations comprising heterogeneous prostate cancers, resulting in vasculogenic mimicry. Hypothesis: A highly regulated cooperativity between the epithelial and fibroblast-like subpopulations is necessary for vasculogenic mimicry in heterogeneous prostate tumors. Specific Aim 3: Determine the role/importance of specific matrix metalloproteinases (MMPs) in prostatic vasculogenic mimicry. Hypothesis: Specific MMPs are critical in the formation of vascular channels and tubular networks by aggressive prostate cancer cells. Significance: The hypothesized presence of tumor- cell lined channels intimately investing neoplasms of the prostate gland, together with their presumptive anastomosis with endothelial-lined vessels of the tumor, provides: 1) a potential new route by which metastases may spread to distant sites, and 2) a means of providing, or supplementing exchange between the tumor and the blood vascular system. As the fundamental cell and molecular mechanisms are identified which underlie the formation, morphology, and functional relationships between these two vascular compartments, it is highly likely that novel strategies will be identified for interfering clinically with both tumor growth and metastasis.