Recently it has been observed in preclinical models that that radiation enhances the recruitment of circulating tumor cells to primary tumors, and results in tumor regrowth after treatment. This process may have implications for clinical radiotherapy, which improves control of a number of tumor types but which, despite continued dose escalation and aggressive fractionation, is unable to fully prevent local recurrences. By irradiating a single tumor within an animal bearing multiple lesions, we observed an increase in tumor cell migration to irradiated and unirradiated sites, suggesting a systemic component to this process. Previous work has identified the cytokine GM-CSF, produced by tumor cells following irradiation, as a key effector of this process. We evaluated the ability of systemic injections of a PEGylated form of GM-CSF to stimulate tumor cell migration. While increases in invasion and migration were observed for tumor cells in a transwell assay, we found that daily injections of PEG-GM-CSF to tumor-bearing animals did not increase migration of cells to tumors, despite the anticipated changes in circulating levels of granulocytes and monocytes produced by this treatment. Combination of PEG-GM-CSF treatment with radiation also did not increase tumor cell migration. These findings suggest that clinical use of GM-CSF to treat neutropenia in cancer patients will not have negative effects on the aggressiveness of residual cancer cells. However, further work is needed to characterize the mechanism by which GM-CSF facilitates systemic recruitment of trafficking tumor cells to tumors.
Radiation therapy Cancer Metastasis GM-CSF
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This work was funded by the National Institutes of Health and the National Cancer Institute of the United States (R01 CA197136, P01 CA067166, S10 OD018208).
This study was funded by the National Institutes of Health and the National Cancer Institute of the United States (R01 CA197136, P01 CA067166).
Compliance with ethical standards
Conflict of interest
M. Vilalta declares that she has no conflict of interest. J. Brune declares that she has no conflict of interest. M. Rafat declares that she has no conflict of interest. L. Soto declares that he has no conflict of interest. E.E. Graves declares that he has no conflict of interest.
All procedures performed in studies involving animal subjects were performed in accordance with the ethical standards of the institutional and national research committee, following approval of an animal protocol by the institutional animal care and use committee.
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