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The goal of this study was to better define the biological impact of mesenchymal stem cells (MSCs) on tumor cell growth. Exogenously administered bone marrow-derived MSCs engraft in established tumors and contribute to the population of tumor associated stromal fibroblasts. While it is not clear what impact MSCs under normal physiological conditions may have on tumor growth, development of anti-cancer strategies using gene-manipulated MSCs have been recently described. Independent studies have shown that MSCs can acquire phenotypes that resemble tumor associated fibroblasts, express potent tumor growth factors, blunt immune responses to allogeneic tumor cells, promote angiogenesis, and even prevent tumor cell apoptosis. We have established a novel multi-fluorescent model system to evaluate the dynamic relationship between MSCs and tumor cells. We have generated human tumor cell lines that stably express red fluorescent protein, and we have derived murine MSCs that stably express germ line green fluorescent protein. In our initial studies, we found that tumor xenografts formed in athymic nude mice by RH30dsRed, a red fluorescent childhood rhabdomyosarcoma cell line, histologically paralleled their human counterparts, and only ∼30% of the tumor mass consisted of red fluorescent RH30dsRed tumor cells. The majority of the xenograft tumor mass was composed of endogenous murine cells suggesting that the biological relationship between human tumor cells and the murine tumor microenvironment was sufficient to replicate human tumor growth. Further studies demonstrated that murine MSCs and human MSCs: (1.) responded similarly to human TGF-β1 exposure by upregulation of alpha-smooth muscle actin, (2.) dynamically interacted with tumor cells in co-cultures through visually apparent physical interactions and altered cell culture morphologies, and (3.) enhanced tumor cell growth rates in co-culture assays. Ongoing studies include a detailed comparison of tumor xenograft biology between human tumor cells alone and co-injections of human tumor cells plus MSCs. Future studies will include two additional red fluorescent tumor cell lines, SKOV-3dsRed (ovarian adenocarcinoma) and MDA-MB-231dsRed (breast adenocarcinoma). In conclusion, our data suggest that MSCs augment tumor cell growth and further investigation in regard to the biological impact of MSCs within tumor microenvironments is warranted.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]