Carcinomas comprise about 90% of all human tumors and arise through the genetic alteration of epithelial cells. Many human carcinomas, including those of the breast, consist of neoplastic epithelial cells intermingled with a complex mixture of cells, including fibroblasts, myofibroblasts, endothelial cells and immune cells, which collectively form the tumor stroma. The supporting stroma of a carcinoma is distinct from that found in the adjacent normal tissue, and as the carcinoma expands, these stromal cells are recruited and induced to proliferate. The presence of stromal cell types within carcinomas is a powerful determinant of the biology of a tumor through its ability to have profound influences on the growth, survival, invasiveness, and metastatic powers of the neoplastic epithelial cells. The presence of these cells has been demonstrated by our laboratory and others to have an essential role in supporting tumor progression; however, the mechanisms of stromal recruitment and how these cells contribute to tumor growth are not well understood. The proposed studies are directed at elucidating the recruitment of stromal cells and the mechanisms by which they influence tumor progression by accomplishing the following: A1. Determining the origins of the tumor-associated stromal cells; A2. Determining the nature of the signals used to recruit stromal precursor cells; A3. Characterizing the heterotypic signals released by recruited stromal cells that influence invasion and metastasis by carcinoma cells; A4. Determining the mechanisms by which mesenchymal stem cells can enhance metastatic ability.
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