The role of host stromal cells in a transplanted orthotopic murine model of diffuse malignant mesothelioma.

摘要

The studies reported in this dissertation attempt to unravel the complex network of interactions between host-derived stromal cells and tumor cells. The goal of this pursuit was to identify specific host-derived cells or extracellular factors that are crucial to the tumor microenvironment and thus a viable target for therapeutic intervention. One of the largest obstacles to this research is the availability of model systems that accurately represent the human disease in not only genotype and gene expression profile, but also in the pattern of stromal cell recruitment and natural history of the tumor including metastasis. A model that accurately reproduces the human disease is also important for assessing the efficacy and potential toxicity of novel therapeutics.;A murine model of diffuse malignant peritoneal mesothelioma was developed and characterized; this model replicates the histopathology and natural history of the human disease when transplanted orthotopically. In contrast to many murine tumor models, pulmonary metastasis occurred late in the disease via routes similar to the human disease. Additionally, this model displays a gene expression profile similar to human malignant mesothelioma.;Recruitment of host stromal cells including endothelial cells and tumor-associated macrophages was observed in the transplanted tumors. The low levels of T H1 cytokines expressed by the cell line and the elevated levels of macrophage recruiting chemokines expressed by tumor spheroids support a mechanism for recruitment early in tumor progression. The coincident increase in expression of the macrophage chemotactic factors and presence of macrophages at the time of tumor establishment and growth suggest that macrophages are important throughout the natural history of this tumor. This is further emphasized by the inhibition of tumor growth following elimination of macrophages by liposome-encapsulated clodronate in mice bearing tumor cells, tumor spheroids, or established tumors.;Finally, the contribution of matrix metalloproteinase 9 to tumor growth and metastasis was assessed. The source of MMP9 was suspected to be macrophages, but this research suggests that another myeloid-derived cell is the source. Despite the multitude of roles MMP9 plays, treatment of mice bearing tumor cells or established tumors with a specific MMP2/MMP9 inhibitor showed did not reduce tumor growth or invasion.