The principal objective of this research is the characterization of the collagenolytic system of malignant tumors, which appear to function in the mechanism of tissue degradation associated with tumor invasion and metastasis. Data from our laboratory suggest the heterogeneity of the """"""""tumor-associated enzymes."""""""" Furthermore, cell separation techniques established the participation of both host and tumor-derived cells in the release of these enzymes. However, the cell source of the enzyme activities and the mechanism of regulation of their synthesis and release is still under investigation. We have also demonstrated that """"""""tumor-host"""""""" cell-cell interaction appears to play a significant role in the enhanced release of collagenolytic activity during the invasive growth of malignant tumors. In light of tumor heterogeneity and the possible influence of cell-cell interactions on the phenotypic characteristics of invasive and metastatic tumors, work is in progress to identify the cell origin of enzyme activities in cultures of isolated tumor clones and in mixtures of these clones. The role of host-tumor cell interactions is being investigated using tumor cell clones as potential stimulators of collagenase release by host fibroblasts of different tissue origins. Preliminary observations using rabbit VX2 carcinoma and the syngeneic model mouse MBT2 and MBT409 bladder carcinoma indicated that host fibroblasts vary in their response to tumor-mediated stimulation of collagenase release. These data suggest that additional factors, such as tumor- or host-derived extracellular matrix components and host immune cells, may be involved in this process. Studies are in progress to assess the role of cell interactions and collagenase release in tumor metastasis using clones of different metastatic potential derived from rat mammary adenocarcinoma 13762NF (MTLn2 and MTLn3). The role of different cell types at the invading tumor zone suggested a more active contribution for the responsive host cells. Furthermore, invasion appears to be associated with a cascade type of interactions between tumor and host cells at certain foci along the invading tumor border. An assessment of the role of individual cell types and characterization of tumor-mediated stimulation of host tissue matrix degradation is in progress. (B)
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