Transplanted hematopoietic stem cells are a promising vehicle for treatment of disease. Recently, cell fusion between bone marrow-derived cells (BMDC) and extra-hematopoietic cells has been demonstrated in both tissue regeneration and tumorigenesis, although the physiologic fate of these cells has not been determined. Our long-range research goal is to understand the role of BMDC fusion in tissue regeneration and tumorigenesis. This application is designed to characterize donor and host contributions to fusion between BMDCs and intestinal tumor epithelium, and to determine if cell fusion plays a direct role in tumor progression. Based upon the observation that myeloid progenitor cells fuse with differentiated hepatocytes, we will identify the discrete subset of BMDCs that is competent to fuse with intestinal epithelium. Next, we will define components of the host environment that synergistically act to optimize fusion between the two cell types. Finally, we will evaluate the impact of BMDC/epithelial cell fusion in promoting tumor growth and metastasis. To this end, we will use BMDC transplantation into wild-type, tumor-bearing and genetically modified mouse strains, plus a combination of FACS, cytogenetics, and whole mount or tissue immunohistochemical analyses. Despite numerous advances in the treatment of colorectal cancer, it remains the second leading cause of cancer related deaths in the United States. This indicates that better therapeutic approaches and a greater understanding of tumorigenesis are needed. The use of stem cells or BMDCs as a therapeutic approach for treating genetic, malignant, and degenerative diseases is promising. Whether cell fusion can be used as a therapeutic delivery vehicle or whether cell fusion results in genetically instable hybrids capable of promoting tumorigenesis is unknown. Therefore determining a role for cell fusion in tumorigenesis is clearly an important first step in determining if a therapeutic approach designed to prevent (or enhance) cell fusion could be used to modulate tumorigenesis. It is feasible that fusion promoting factors, or the fusion products themselves, may be useful targets for preventing tumor progression. ? ? ?
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