Abstract
Abstract Background: Radiation increases engraftment of human bone-marrow derived mesenchymal stem cells (MSC) in tumors and this effect is augmented following repeated doses of radiation. We have recently demonstrated that MSC increase formation of mammospheres, which are enriched with radiation resistant tumor-initiating cells. Thus, we hypothesized that MSC may impact radiation therapy response through enhanced survival of tumor-initiating cells. Materials & Methods: To evaluate the impact of MSC on radiation response we performed in vitro clonogenic survival assays using 2D and 3D clonogenic assays. Colony (2D) and sphere (3D) formation was quantified following irradiation of different cell lines (breast, lung, head and neck and cervix) at 2, 4 and 6 Gy in the presence of MSC conditioned media. In vivo, MSC were co-injected subcutaneously at increasing percentages with 4T1 murine breast cancer cells in BALB/c mice. The effects of MSC on radiation response were evaluated by examination of tumor size and weight following tumor irradiation at 2 and 5 Gy. Results: In vitro 2D clonogenic cell survival assays demonstrated that MSC conditioned media increased survival of breast (MDA231), lung (H460), head and neck (HN5), and cervical (SiHa) cancer cells following irradiation with 2 and 4 Gy as compared to control fibroblast conditioned media. Moreover, MSC conditioned media increased the number of HMLE (breast normal ephitelial cells) and SUM149 (breast cancer cells) mammospheres formed (55 vs 195and 263 vs 1054, respectively) and increased clonogenic survival of mammospheres after 2, 4 and 6 Gy compared to serum-free media. In vivo, irradiation with 5 Gy reduced murine breast 4T1tumors weight by 75% as compared to control untreated tumors. However, tumors co-injected with MSC did not significantly respond to 5 Gy. Discussion: MSC increase tumor resistance to radiation therapy in vivo and in vitro in 2D and 3D cultures. This effect is mediated at least in part by paracrine factors secreted by MSC. Our results here described suggest that MSC secrete factors which activate survival pathways on cancer cells exposed to sub-lethal radiation doses. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr PD02-07.
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