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Origins of Mammary Tumor Stromal Cells
When examined histologically, breast cancers are almost invariably found to be composed of neoplastic cells and a variety of non-neoplastic cells that have been recruited into the tumor mass. These apparently normal cells, including endothelial cells, pericytes, fibroblasts, myofibroblasts, mast cells and macrophages, collectively form the tumor stroma. These stromal cells appear to provide physiologically important functions to the cancer cells; however, the origins of the stromal cells are in large part unclear. The proposed research examines the possibility that many types of stromal cells are recruited directly from the circulation, which is known to carry a variety of stromal cell precursors. Identification of such circulating precursors will itself represent a substantial advance in our understanding of breast cancer pathogenesis. A successful demonstration that circulating stromal cell precursors are preferentially recruited into the tumor cell mass and not into normal, non-neoplastic tissues may make possible a new form of anti-tumor therapy in which toxin-activating genes are inserted into stromal cell precursors prior to introduction of the latter into the circulation of a tumor-bearing host. Following recruitment of these cells into the tumor mass, pro-toxins can then be injected into the host, whereupon they will be activated in the tumor-associated stroma and kill cancer cells through bystander-effect killing.
The majority of cells in most mammary tumors are cells of mesenchymal rather than epithelial origin. These stromal cells include fibroblasts, myofibroblasts, endothelial cells, pericytes, macrophages, lymphocytes, and mast cells. A diverse body of information provides clear indication that these stromal cells provide various types of biological support to the neoplastic epithelial cells. Indeed, in our own laboratory, we have found that the fibroblasts prepared from human breast carcinomas are far more potent in aiding in the growth of xenograft tumors than are normal human mammary stromal fibroblasts. We propose to determine the origin of many of these stromal cells. While some may well derive from the adjacent normal mammary tissue, we have reason to believe that most arise in the bone marrow, from which they are actively recruited by the carcinoma cells. We intend to determine i) whether the majority of mammary tumor stromal cells derive from the marrow; ii) how breast carcinomas succeed in this recruitment; and iii) whether this recruitment makes possible the targeted delivery of certain therapeutic agents to mammary carcinomas.