Degradation of extracellular matrices during tumor invasion and, in particular, the involvement of collagenolytic enzymes, has been documented in this and other laboratories. Recent studies have focused on the role of host fibroblast-tumor cell interactions in regulation of collagenase activity and have shown that: (1) tumor cells produce a factor which dramatically stimulates collagenase production by fibroblasts; (2) the stimulatory factor is present at the tumor cell surface; (3) the factor can be extracted from cell membranes by detergent; (4) it is hydrophobic in nature, i.e., it can be reintercalated into lipid vesicles; and (5) the appearance of the tumor cell factor in conditioned medium is enhanced by exposure of the tumor cells to matrix deposited by fibroblasts. Based on these observations, it is proposed that the factor contains a hydrophobic domain which is attached directly to the tumor cell plasma membrane and a hydrophilic domain containing the active site which interacts with a receptor on the fibroblast surface, causing stimulation of collagenase production. Under certain conditions, e.g., exposure to fibroblast matrix, the hydrophilic domain would be cleaved from the tumor cell plasma membrane and appear in conditioned medium. Thus, a detailed investigation of the regulation of collagenase production by fibroblast-tumor cell interactions is intended. Fibroblasts and human tumor cells will be used to: (1) generate monoclonal antibodies to the tumor cell factor and use these to develop a sensitive assay and to purify the factor; (2) examine the relationship between membrane-bound and soluble forms of the factor; (3) study the lipophilic properties of the membrane-bound factor; and (4) begin a study of its interaction with putative receptors on the fibroblast surface. These experiments will lead in the future to a detailed investigation at the molecular level of regulation of factor production in tumor cells, its effect on fibroblast collagenase production, and its role in the invasive properties of tumor cells. This knowledge will aid in our understnding of the metastatic process and thus the development of therapeutic techniques. (W)
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