Involvement of collagenolytic enzymes in degradation of extracellular matrices during tumor invasion has been documented by several investigators. Past studies have shown that fibroblasts are stimulated to produce type I collagen-degrading enzyme by a tumor cell factor (TCSF) present on the tumor cell membrane. Subsequently, using a human tumor cell line LX-1, monoclonal antibodies were raised against TCSF and the factor was purified. TCSF has a mol wt. of 58 kD, and is present on the outer surface of tumor cells but not fibroblasts. It stimulates collagenase and collagenase mRNA production in fibroblasts. Several low mol wt. proteins are present in conditioned medium from tumor cells which are immunologically cross-reactive with TCSF, suggesting their generation by proteolytic cleavage of the membrane TCSF. Based on these findings we plan: 1) To obtain internal peptide sequences for TCSF to be used for conformation of the identity of cDNA clones and for design of oligonucleotide probes. 2) To characterize the cDNA clone(s) for TCSF that we have already obtained and others that will be obtained in the future for use in the study of its homology with other agents, particularly collagenase stimulatory agents, and its expression in normal and tumor cells and tissues. 3) To screen a variety of normal and tumor tissues to establish its distribution and possible correlations with degrees of tumor invasion. In addition, we will begin to examine other potential properties of TCSF. These experiments will yield further information regarding the molecular nature and properties of TCSF, and the regulation of its production in normal vs. neoplastic tissue. In turn this knowledge may lead to the development of therapeutic methods involving prevention of its action.
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