Role of matrix, fibroblasts and type IV collagenases in tumor progression and invasion.

We have studied the role of the extracellular matrix and host cells in tumor progression and tumor invasion. Our results emphasize the importance of tumoral cell-host cell interactions during this process. Addition of human fibroblasts and/or basement membrane components to human mammary adenocarcinoma cells, when injected into athymic nude mice, results in an increase of take and growth rate of the tumors. Peritumoral extracellular matrix is remodeled through multiple mechanisms: overproduction of matrix components by fibroblasts, enhanced fibroblasts proliferation, modulation of interstitial collagenase production by fibroblasts and retraction of the matrix by tumoral cells. The degradation of basement membranes during the metastatic process is often associated with the secretion of proteolytic enzymes. The 72 kDa type IV collagenase, a metalloproteinase, can be produced by some tumoral cells. However, it appears also to be secreted by peritumoral stromal fibroblasts under the influence of tumoral cells. We have demonstrated the existence of a binding site for this enzyme on the membrane of mammary tumoral cells. These results suggest a cooperation between tumor cells and fibroblasts during basement membrane destruction.