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PMID: 25892230 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Intratumoral myeloid cells regulate responsiveness and resistance to antiangiogenic therapy.

Cell reports ·Vol. 11 ·No. 4 ·2015-04-28 ·Pages 577-91

Rivera LB, Meyronet D, Hervieu V, Frederick MJ, Bergsland E, Bergers G

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.

MeSH Terms
Angiogenesis Inhibitors/pharmacology,therapeutic use Animals Cells, Cultured Chemokines, CXC/metabolism Drug Resistance, Neoplasm Humans Mammary Glands, Human/blood supply Mice Myeloid Cells/drug effects,metabolism Neovascularization, Pathologic/drug therapy,metabolism Phosphatidylinositol 3-Kinases/metabolism Receptors, Vascular Endothelial Growth Factor/antagonists & inhibitors,metabolism Vascular Endothelial Growth Factor A/metabolism
Chemicals
Angiogenesis Inhibitors CXCL14 protein, mouse Chemokines, CXC Vascular Endothelial Growth Factor A Phosphatidylinositol 3-Kinases Receptors, Vascular Endothelial Growth Factor
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Rivera Lee B
Department of Neurological Surgery, Brain Tumor Research Center, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA.
Meyronet David
Université Lyon 1, Centre de Pathologie et Neuropathologie Est, Hospices Civils de Lyon, Bron Cedex 69677, France.
Hervieu Valérie
Université Lyon 1, Service d'Anatomie Pathologique, Hôpital Édouard Herriot, Hospices Civils de Lyon, Lyon Cedex 69003, France.
Frederick Mitchell J
Department of Head and Neck Surgery, Research Division of Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Bergsland Emily
Department of Medicine, UCSF Mount Zion Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA.
Bergers Gabriele
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.
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Article Info
Journal
Cell reports
Abbr.
Cell Rep
ISSN
2211-1247
DOI
10.1016/j.celrep.2015.03.055
Email
gabriele.bergers@ucsf.edu
Published
2015-04-28
Epub
2015-00-16
Pages
577-91
Language
English
Region
United States
NLM ID
101573691
PMCID
PMC4438771
Subset
IM
Grants
NCI NIH HHS · R01 CA099948 · United States
NCI NIH HHS · U54 CA163155 · United States
NCI NIH HHS · U54CA163155 · United States
NCI NIH HHS · R01 CA188404 · United States
NCI NIH HHS · T32CA108462-09 · United States
NCI NIH HHS · T32 CA108462 · United States
External Links
PubMed source DOI: 10.1016/j.celrep.2015.03.055 PMC Full Text View journal details
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