The long term goal is to elucidate the pathogenesis of tumor stroma generation, and its relation to normal wound healing. Carcinomas are comprised of neoplastic cells (parenchyma) and the connective tissue (stroma) in which they are dispersed. Tumors require stroma if they are to grow but the mechanisms of stroma induction are poorly understood. Analysis of stroma generation in transplantable animal tumors has established important similarities between tumor stroma generation and normal wound healing, suggesting the hypothesis that tumors induce stroma by activating wound healing. The earliest event in tumor stroma generation is hyperpermeability of local blood vessels to plasma proteins. This leads to extravasation of plasma proteins, including fibrinogen which clots to form an extravascular fibrin gel. This fibrin gel provides a provisional matrix into which inflammatory cells, fibroblasts, and capillaries migrate, eventually replacing it with mature, vascularized, proteoglycan- and collagen-rich stroma. Wound healing evolves through similar steps, beginning with spillage of blood from injured vessels. Once fibrin is deposited in tissues, angiogenesis, fibroblast infiltration, and deposition of matrix follow pari passu. At present, evidence for a wound healing model of stroma generation is based on analogy with transplantable animal tumors which may afford poor models for human cancer. Also, tumor stroma, like tumor cells, may progress over time. Thus, tumor stroma and the process of its generation in animals may resemble the human situation only at late stages of tumor progression. In order to investigate the pathogenesis of tumor stroma generation in man and to determine its relationship to wound healing, we will study human tumors and healing wounds for molecular components that in animal systems mark discrete, successive steps in the evolution of tumor stroma generation and wound healing. These marker proteins include vascular permeability factor, extravasated plasma proteins, extravascular fibrin, fibronectin and its splicing variants, and altered forms and amounts of other matrix components; e.g., collagens I and IV, decorin, versican, hyaluronan. Using immunohistochemistry, in situ hybridization and RNase protection assays, we will determine (1) whether and to what extent several common, medically important human tumors (originating in the colon, breast and skin), benign and at various stages of malignant progression, primary and metastatic, express and/or deposit protein markers that define successive stages of tumor stroma generation and wound healing in animal systems; (2) at what stages in human tumor progression each of these appears; (3) whether similar molecules are present in normal human wound healing; and (4) whether these proteins appear in normal or abnormal amounts and time sequence when wound healing is overexuberant (hypertrophic scars of keloids) of fails (poorly healing leg ulcerations).
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