Transplanted Stem Cells and Tumor Progression

描述（由申请人提供）：移植的造血干细胞是治疗疾病的有前途的载体。 最近，骨髓来源的细胞（BMDC）和造血外细胞之间的细胞融合已被证明在组织再生和肿瘤发生，虽然这些细胞的生理命运尚未确定。 我们的长期研究目标是了解BMDC融合在组织再生和肿瘤发生中的作用。 该应用程序旨在表征供体和宿主对BMDC和肠肿瘤上皮细胞之间融合的贡献，并确定细胞融合是否在肿瘤进展中起直接作用。 基于骨髓祖细胞与分化的肝细胞融合的观察，我们将鉴定能够与肠上皮融合的BMDC的离散子集。 接下来，我们将定义协同作用以优化两种细胞类型之间融合的宿主环境的组分。 最后，我们将评估BMDC/上皮细胞融合在促进肿瘤生长和转移中的影响。 为此，我们将使用BMDC移植到野生型，荷瘤和遗传修饰的小鼠品系，加上流式细胞仪，细胞遗传学和整体或组织免疫组化分析的组合。 尽管结肠直肠癌的治疗取得了许多进展，但它仍然是美国癌症相关死亡的第二大原因。 这表明需要更好的治疗方法和对肿瘤发生的更深入了解。 使用干细胞或BMDC作为治疗遗传性、恶性和退行性疾病的治疗方法是有希望的。 细胞融合是否可用作治疗递送载体或细胞融合是否导致能够促进肿瘤发生的遗传不稳定的杂交体尚不清楚。 因此，确定细胞融合在肿瘤发生中的作用显然是确定设计用于防止（或增强）细胞融合的治疗方法是否可用于调节肿瘤发生的重要的第一步。 融合促进因子或融合产物本身可能是预防肿瘤进展的有用靶点。

DESCRIPTION (provided by applicant): 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.