Tumor invasion and metastasis is associated with host tissue degradation. Several laboratories, including ours, have demonstrated the role of collagenolytic enzymes in this process. The expression of collagen-degrading enzymes is invariably microenvironmental, and it is likely that host:tumor cell interactions are important in modulating this activity. Our recent studies, which have focused on the """"""""invasion zone"""""""" of various tumors, have showed increased numbers of mast cells (MC) and macrophages (Mac) at the tumor periphery as well as association of MC degranulation with localized stromal lysis. In the renewal application, we seek to examine the role of tumor cell-host fibroblast interactions, and the effects of MC and Mac on tumor cells and stromal fibroblasts in relation to their collagenolytic, invasive and metastatic properties using rat mammary adenocarcinoma and certain human neoplasms. In these studies we propose to; (1) characterize tumor-derived cytokines (M - 53K and 15K, recently isolated in our laboratory), which stimulated the collagenolytic activity of syngeneic fibroblasts; (2) examine the role of MC- and Mac-derived factors in modulating the expression of collagenolytic enzymes by tumor cells and by select subpopulations of stromal fibroblasts which appear to be responsive to these factors; (3) determine the effect of experimentally-induced MC degranulation, and Mac-derived products, on the invasive and metastatic behavior of tumor cell clones of different metastatic potential; (4) determine whether tumor cells possess histamine, heparin, IL-l and TNF receptors and how the stimulation of such receptors might modulate their proliferative, collagenolytic and invasive properties; and (5) study the distribution and frequency of MC and Mac in a variety of human neoplasms and correlate these observations to the distribution of immunoreactive collagenase in these tumors. The results of these studies will indicate the importance of host- tumor cell interactions in collagenolytic mechanisms involved in matrix degradation, and may provide new therapeutic approaches for modifying the normal function of host MC and/or Mac that might be beneficial in the management of certain neoplasms.
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