Solid tumors are comprised of malignant cells and stroma in variable proportions. Tumor stroma, in turn, is connective tissue composed of fibroblasts, collagen, blood vessels, and sometimes inflammatory cells. In order to grow beyond a size of approximatey 1 mm, solid tumors must induce stroma. However, the mechanisms of tumor stroma generation are poorly understood. Recent studies have established that crosslinked fibrin and fibronectin are regular early components of tumor stroma. Indeed, tumors regularly induce a fibrin-fibronectin gel that serves as a provisional matrix which fibroblasts and blood vessels infiltrate. Over time, the fibrin-fibronectin provisional matrix is transformed into mature collagenous stroma. This proposal is concerned with the pathogenesis of tumor stroma generation and particularly with the mechanisms by which tumor cells and benign host fibroblasts interact to transform the fibrin-fibronectin gel into collagenous stroma. We will examine a number of factors that are expected to govern and regulate fibroblast and tumor cell collagen synthesis under conditions designed to similate the tumor microenvironment as it is found in vivo. These environmental factors include fibrin-fibronectin gels of defined composition as well as degradation products of such gels, relative hypoxia, and the presence of tumor and/or fibroblast products, all of which may be expected to modulate collagen synthesis. Indeed, preliminary data indicate that fibroblasts cultured in fibrin gels alter their collagen synthesis significantly as compared with the same cells cultured under standard tissue culture conditions on plastic. We expect these experiments to provide new insights into the important problem of tumor stroma formation; they are also likely to shed new light on the mechanism of wound healing, a closely related process. (N)
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