THE DESMOPLASTIC RESPONSE TO TUMOR INVASION

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The desmoplastic response to tumor invasion is an important though poorly understood collagenous host reaction responsible for the hard lump appearance of many cancers. In human breast carcinoma, approximately 80% of cases are associated with intense desmoplasia, a response which promotes early clinical detection. Both the mechanism of this response and its effect on tumor invasion and metastasis are not known, but previous studies have indicated that the desmoplastic reaction is composed of numerous host myofibroblasts and a unique collagen profile with relatively high amounts of Type V collagen. The aims of this research project are three-fold. The first aim is to characterize and purify a myofibroblast growth factor elaborated by invasive tumor cells. Human breast carcinoma tissue of the desmoplastic variety and cell lines such as MCF-7 and MDA-MB-134-VI will be studied for the presence of such factors by chemotaxis, mitogenesis, and myofibroblast-differentiating assays. Non-desmoplastic human breast carcinoms (medullary type) and cell lines derived from them will serve as controls. The second aim is to further characterize the desmoplastic response biochemically, specifically identifying inhibitors to tumor proteases such as Type IV collagenase, cathepsins, and plasminogen activator, all of which have been implicated in the invasive process. Human breast carcinoma tissue of the desmoplastic variety again will serve as source from which to extract these inhibitors to invasion. The demonstration of high amounts of protease inhibitors within desmoplastic tissue would suggest that one purpose of the response is to limit the local spread of tumor. The final aim of this study is to examine the effect of the desmoplastic response on distant metastasis. To achieve this, a new quantitative model of desmoplasia has been developed in the C57 BL/6 mouse, utilizing the syngeneic transplantable tumor, BL6 melanoma, and 14C proline instilled intraperitoneally. Host collagen synthesis is measured at the primary site and perturbated with blockers of collagen synthesis. The effect on pulmonary metastases will be determined. The long-term purpose then is insight into the mechanism and meaning of desmoplasia. (A)