The role of granulocyte macrophage colony stimulating factor (GM-CSF) in radiation-induced tumor cell migration

Abstract

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.

Preliminary Study of the Effect of Stereotactic Body Radiotherapy (SBRT) on the Immune System in Lung Cancer Patients Unfit for Surgery: Immunophenotyping Analysis

“…Even though some studies have found that radiation induced stimulation of cytokine granulocyte-macrophage colony-stimulating factor [29,30], all these studies have been tested with large fields as are used in conventional radiation therapy. However, SBTR is a technique which allows the delivery of high doses in small fields, so it is unclear whether radiation delivered by SBRT can produce an increase of granulocyte levels.…”

A Combination of Cabozantinib and Radiation Does Not Lead to an Improved Growth Control of Tumors in a Preclinical 4T1 Breast Cancer Model

“…However, in livers from mice that were treated with Cabozantinib with and without irradiation, this type of cells was reduced in prevalence or entirely absent, in line with the capability of Cabozantinib to antagonize MDSC as shown in other models ( 7 , 8 ). Moreover, enhanced release of GM-CSF following irradiation of 4T1 tumors was shown to attract circulating tumor cells into the tumor bed of irradiated tumors and unirradiated secondary tumor sites, contributing to tumor re-growth ( 24 ). Cabozantinib, on the other hand, resulted in a reduced tumor growth ( Figure 4 ), thus pointing to a role for GM-CSF and MDSC recruitment in our model and an explanation for the radioresistance of tumors treated with irradiation alone.…”

Targeting Innate Immunity to Enhance the Efficacy of Radiation Therapy

“…In addition to expression of complement, RT has been shown to increase the expression of a number of cytokines and chemokines. Aside from the previously mentioned type I interferons, RT has been shown to induce immune cells within the tumor including TAMs and CD8+ T cells and NK cells and others to produce inflammatory cytokines including tumor necrosis factor alpha (TNF-α) (70), interleukin-1 (71), interleukin-6 (72, 73), interferon-gamma (IFN-γ) (3, 74), macrophage colony stimulating factor 1 (CSF-1, M-CSF) (75), and granulocyte macrophage colony stimulating factor (GM-CSF) (76, 77). These cytokines are critical for establishing inflammation at the irradiated site as well as induction of a cytotoxic CD8+ T cell response.…”