Epithelial cells up-regulate matrix metalloproteinases in cells within the same mammary carcinoma that have undergone...

A metastatic rat mammary carcinoma cell line, BC1, contains cells that have retained epithelial differentiation characteristics and metaplastic cells that have undergone an epithelial-mesenchymal transition. These two subpopulations cooperate to degrade collagen. We have used novel PCR assays to quantitate, for the first time, absolute levels of the mRNAs encoding matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in cell and tumor samples. BC1 tumors expressed high levels of the collagenase-3, TIMP-2, stromelysin-1, and gelatinase B genes and low levels of the stromelysin-2 and TIMP-1 genes. This pattern of expression was repeated in cultures of BC1 and cultures containing mixed clones of epithelial cells and metaplastic cells. In both BC1 and the biclonal cultures, metaplastic cells were the main source of collagenase-3, stromelysin-1 and stromelysin-2, whereas TIMPs were equally distributed and epithelial cells were the main source of gelatinase B. High levels of all four MMP mRNAs in metaplastic cells were dependent on coculture with epithelial cells, suggesting the production of an inducing factor by the epithelial cells. In contrast, gelatinase B mRNA was produced at a high level by epithelial cells in the absence of metaplastic cells. TIMP-2 mRNA was abundant in both subpopulations grown alone and did not change substantially upon coculture. Thus, the interclonal cooperativity to degrade collagen in BC1 cells required the induction of MMPs in metaplastic cells by epithelial cells. Interclonal cooperativity may be important to the progression of neoplastic tumors, a feature of which is phenotypic heterogeneity.