Radiation enhances engraftment of mesenchymal stem cells in murine 4T1 tumors Free

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Mesenchymal stem cells (MSCs) migrate and proliferate within tumors as well as at other sites of inflammation. MSCs engineered to express IFN-β have been shown to reduce tumor burden and extend survival in murine breast cancer, leukemia and glioma models. Clinical trials are under development but this strategy could be limited by non-specific migration of MSCs to other sites of inflammation. Radiation increases expression of inflammatory cytokines and could be used to enhance engraftment of MSCs in tumors. To investigate this, we implanted 2 x 10⁵ 4T1 cells expressing renilla luciferase into bilateral hindlimbs of Balb/C mice. Nine days later, a dose of 1 or 2 Gy was delivered with ⁶⁰Co to the right hindlimb. Control mice were not irradiated. Ten days after tumor implantation, 4 x 10⁵ MSCs transduced with an adenoviral vector expressing firefly luciferase were injected intravenously. Mice were then serially monitored with bioluminescent imaging for expression of renilla and firefly luciferase.

Two days after radiation, levels of MSC engraftment using luciferase imaging were 25% higher in tumors receiving 2 Gy (p=0.004, two-sided t-test) and 22% higher in tumors treated to 1 Gy (p=0.03) as compared to contralateral unirradiated tumors. Levels of MSC engraftment were the same in the right and left leg in unirradiated mice. Radiation did not appear to contribute to engraftment in the contralateral limb as MSC levels were similar in the unirradiated limb of mice treated with radiation and in unirradiated mice. At 4 and 6 days after treatment, there were no statistically significant differences in absolute levels of MSC engraftment. However, if normalization to renilla luciferase was performed to account for tumor shrinkage in response to radiation, there was a relative increase in MSCs in tumors radiated to 2 Gy at 4 days (1.4 fold higher in radiated limb, p=0.08) and 6 days (1.5 fold higher in radiated limb, p=0.003) after treatment. In conclusion, MSCs preferentially engraft in 4T1 tumors after a single low dose fraction of radiation. Additional experiments to maximize this effect are in progress. The concept proposed could be a useful strategy to selectively enhance delivery of anti-tumor agents in MSC to tumor sites.