Degradation of the extracellular matrix in normal tissue surrounding a tumor leads to invasion and ultimately metastasis. It is this process that makes cancers malignant. Previous studies have shown that the proteolytic enzymes, matrix metalloproteinases (MMPs) and plasminogen activators (PAs), as well as their inhibitors, tissue inhibitors of metalloproteinases (TIMPs) and plasminogen activator inhibitors (PAIs), are involved in the degradation of the extracellular matrix. Preliminary data suggest that degradation of the extracellular matrix is controlled by tumor cell-adjacent cell modulation of these extracellular matrix degrading enzymes and their inhibitors. We will specifically examine this interaction by 1) identifying and quantifying the secretion of MMPs, PAs, TIMPs and PAIs by murine syngeneic normal dermal keratinocytes, dermal fibroblasts, melanocytes (Mel-ab), the poorly invasive and poorly metastatic B16 melanoma and the highly invasive and highly metastatic BL6 variant; 2) comparing secretion and activation of MMPs and PAs and comparing secretion of these inhibitors in cocultures of keratinocytes and fibroblasts with melanocytes, B16 and BL6 melanoma cells with the individual cell cultures and 3) identifying components that influence the balance between activated MMPs PAs and their inhibitors that lead to invasion and eventually metastasis.
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