DESMOPLASTIC RESPONSE TO TUMOR INVASION

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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. This competitive renewal will continue to study both the pathogenesis of the response as well as the effects of the response on tumor invasion and metastasis. The first basic aim will be to further characterize and purify the 25,000 M.W. myofibroblast growth factor, compare it to known growth factors, demonstrate a role for this factor in the pathogenesis of the response with in vivo studies of myofibroblast expression of c-myc, c-fos, elastin, Type I, and Type V collagen genes and will in vivo studies with the desmoplasia-inducing c-Has-ras transfected high p21 MCF-7 human breast carcinoma cell line. The second basic aim will be to study the role of the 40,000 M.W. desmoplastic inhibitor of metalloproteinases (DIMP) in conferring to the desmopastic response a partial but not total resistance to tumor invasion and metastasis. This will involve a detailed comparison of DIMP with TIMP (tissue inhibitor of metalloproteinases) and an evaluation of a possible mechanism which would allow successful tumor collagenolysis even whether the desmoplastic response, being only partially successful in inhibiting invasion, ultimately exerts selection pressure for subpopulations of the primary tumor with increased metastatic potential.