TUMOR CELL-DESMOPLASTIC RESPONSE INTERACTIONS

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The desmoplastic response to tumor invasion is a poorly understood host myofibroblast-mediated collagenous response responsible for the "hard lump" appearance of many human cancers. Recent observations have suggested that the response exerts significant inhibitory effects on tumor invasion and metastasis mediated by high myofibroblast-secreted metalloproteinase inhibitory activity. The response fails, however, to totally block invasion and metastasis. This research career development award proposal will focus in depth on the nature of these tumor metalloproteinase- desmoplastic inhibitor interactions which ultimately influence metastasis. Aim #1 will examine the uniqueness of the myofibroblast-derived metalloproteinase inhibitor activity present within the desmoplastic response (DIMP). Since most tissues are not resistant to invasion yet contain ubiquitous tissue inhibitors of metalloproteinases (TIMP), this aim will involve a detailed comparison of DIMP with TlMP with respect to possible parameters (increased molar inhibitory activity of Type IV and Type I collagenase, increased rate of synthesis, and increased tissue affinity) which could account for DIMP's selective contribution to tumor invasion resistance. Aim #2 will examine a possible mechanism of interaction between tumor cell collagenase and DIMP which would allow some tumor cells to carry out successful collagenolysis and invasion even in the presence of a vast excess of desmoplastic metalloproteinase inhibitory activity. Aim #3 will examine whether the desmoplastic response, being only partially successful in inhibiting tumor invasion, ultimately exerts selection pressure for a more aggressive tumor. Desmoplastic response-selected sublines will be derived from pulmonary metastases and several of their relevant metastatic phenotypic features examined.