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Cell Rep. 2015 Apr 28;11(4):577-91. doi: 10.1016/j.celrep.2015.03.055. Epub 2015 Apr 16.

Intratumoral myeloid cells regulate responsiveness and resistance to antiangiogenic therapy.

Author information

1
Department of Neurological Surgery, Brain Tumor Research Center, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA.
2
Université Lyon 1, Centre de Pathologie et Neuropathologie Est, Hospices Civils de Lyon, Bron Cedex 69677, France.
3
Université Lyon 1, Service d'Anatomie Pathologique, Hôpital Édouard Herriot, Hospices Civils de Lyon, Lyon Cedex 69003, France.
4
Department of Head and Neck Surgery, Research Division of Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
5
Department of Medicine, UCSF Mount Zion Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA.
6
Department of Neurological Surgery, Brain Tumor Research Center, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA. Electronic address: gabriele.bergers@ucsf.edu.

Abstract

Antiangiogenic therapy is commonly used in the clinic, but its beneficial effects are short-lived, leading to tumor relapse within months. Here, we found that the efficacy of angiogenic inhibitors targeting the VEGF/VEGFR pathway was dependent on induction of the angiostatic and immune-stimulatory chemokine CXCL14 in mouse models of pancreatic neuroendocrine and mammary tumors. In response, tumors reinitiated angiogenesis and immune suppression by activating PI3K signaling in all CD11b+ cells, rendering tumors nonresponsive to VEGF/VEGFR inhibition. Adaptive resistance was also associated with an increase in Gr1+CD11b+ cells, but targeting Gr1+ cells was not sufficient to further sensitize angiogenic blockade because tumor-associated macrophages (TAMs) would compensate for the lack of such cells and vice versa, leading to an oscillating pattern of distinct immune-cell populations. However, PI3K inhibition in CD11b+ myeloid cells generated an enduring angiostatic and immune-stimulatory environment in which antiangiogenic therapy remained efficient.

PMID:
25892230
PMCID:
PMC4438771
DOI:
10.1016/j.celrep.2015.03.055
[Indexed for MEDLINE]
Free PMC Article

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