CSF1R Signaling Blockade Stanches Tumor-Infiltrating Myeloid Cells and Improves the Efficacy of Radiotherapy in Prostate Cancer
Top Cited Papers
- 30 April 2013
- journal article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 73 (9), 2782-2794
- https://doi.org/10.1158/0008-5472.can-12-3981
Abstract
Radiotherapy is used to treat many types of cancer, but many treated patients relapse with local tumor recurrence. Tumor-infiltrating myeloid cells (TIM), including CD11b (ITGAM)+F4/80 (EMR1)+ tumor-associated macrophages (TAM), and CD11b+Gr-1 (LY6G)+ myeloid-derived suppressor cells (MDSC), respond to cancer-related stresses and play critical roles in promoting tumor angiogenesis, tissue remodeling, and immunosuppression. In this report, we used a prostate cancer model to investigate the effects of irradiation on TAMs and MDSCs in tumor-bearing animals. Unexpectedly, when primary tumor sites were irradiated, we observed a systemic increase of MDSCs in spleen, lung, lymph nodes, and peripheral blood. Cytokine analysis showed that the macrophage colony-stimulating factor CSF1 increased by two-fold in irradiated tumors. Enhanced macrophage migration induced by conditioned media from irradiated tumor cells was completely blocked by a selective inhibitor of CSF1R. These findings were confirmed in patients with prostate cancer, where serum levels of CSF1 increased after radiotherapy. Mechanistic investigations revealed the recruitment of the DNA damage-induced kinase ABL1 into cell nuclei where it bound the CSF1 gene promoter and enhanced CSF1 gene transcription. When added to radiotherapy, a selective inhibitor of CSF1R suppressed tumor growth more effectively than irradiation alone. Our results highlight the importance of CSF1/CSF1R signaling in the recruitment of TIMs that can limit the efficacy of radiotherapy. Furthermore, they suggest that CSF1 inhibitors should be evaluated in clinical trials in combination with radiotherapy as a strategy to improve outcomes. Cancer Res; 73(9); 2782–94. ©2013 AACR.Keywords
Other Versions
This publication has 51 references indexed in Scilit:
- Macrophage Delivery of an Oncolytic Virus Abolishes Tumor Regrowth and Metastasis after Chemotherapy or IrradiationCancer Research, 2013
- c-Abl Is an Upstream Regulator of Acid Sphingomyelinase in Apoptosis Induced by Inhibition of Integrins αvβ3 and αvβ5PLOS ONE, 2012
- Targeting distinct tumor-infiltrating myeloid cells by inhibiting CSF-1 receptor: combating tumor evasion of antiangiogenic therapyBlood, 2010
- Myeloid-Derived Suppressor Cells: Linking Inflammation and CancerThe Journal of Immunology, 2009
- Myeloid-derived suppressor cells as regulators of the immune systemNature Reviews Immunology, 2009
- A Destructive Cascade Mediated by CCL2 Facilitates Prostate Cancer Growth in BoneCancer Research, 2009
- Subsets of Myeloid-Derived Suppressor Cells in Tumor-Bearing MiceThe Journal of Immunology, 2008
- Improving chemotherapeutic drug penetration in melanoma by imatinib mesylateJournal of Dermatological Science, 2008
- The role of myeloid cells in the promotion of tumour angiogenesisNature Reviews Cancer, 2008
- Discovery of a Cytokine and Its Receptor by Functional Screening of the Extracellular ProteomeScience, 2008