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PMID: 23418320 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

CSF1R signaling blockade stanches tumor-infiltrating myeloid cells and improves the efficacy of radiotherapy in prostate cancer.

Cancer research ·Vol. 73 ·No. 9 ·2013-05-01 ·Pages 2782-94

Xu J, Escamilla J, Mok S, David J, Priceman S, West B, Bollag G, McBride W, Wu L

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.

MeSH Terms
Animals Cell Line Cell Line, Tumor Cell Movement Chromatin/metabolism DNA Damage Humans Immunohistochemistry/methods Macrophages/cytology Male Mice Mice, Inbred C57BL Microscopy, Fluorescence/methods Myeloid Cells/cytology Neoplasm Transplantation Prostatic Neoplasms/metabolism,radiotherapy Radiotherapy/methods Receptor, Macrophage Colony-Stimulating Factor/metabolism Signal Transduction
Chemicals
Chromatin Receptor, Macrophage Colony-Stimulating Factor
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Xu Jingying
Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California 90095-1735, USA.
Escamilla Jemima
Mok Stephen
David John
Priceman Saul
West Brian
Bollag Gideon
McBride William
Wu Lily
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Article Info
Journal
Cancer research
Abbr.
Cancer Res
ISSN
1538-7445
DOI
10.1158/0008-5472.CAN-12-3981
Published
2013-05-01
Epub
2013-00-15
Pages
2782-94
Language
English
Region
United States
NLM ID
2984705R
PMCID
PMC4097014
Subset
IM
Grants
NCRR NIH HHS · UL1 RR033176 · United States
NCATS NIH HHS · UL1 TR000124 · United States
NCI NIH HHS · P50 CA092131 · United States
NCI NIH HHS · R01 CA101904 · United States
NCRR NIH HHS · 1UL1RR033176 · United States
Corrections
CommentIn
PMID: 24331512
External Links
PubMed source DOI: 10.1158/0008-5472.CAN-12-3981 PMC Full Text View journal details
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