CCL2/CCR2 Regulates the Tumor Microenvironment in HER-2/neu-Driven Mammary Carcinomas in Mice.
Chronic inflammation is a hallmark of cancer. Inflammatory chemokines, such as C-C chemokine ligand 2 (CCL2), are often present in tumors but their roles in cancer initiation and maintenance are not clear. Here we report that CCL2 promotes mammary carcinoma development in a clinically relevant murine model of breast cancer. Targeted disruption of Ccl2 slowed the growth of activated Her2/neu-driven mammary tumors and prolonged host survival. Disruption of Ccl2 was associated with a decrease in the development and mobilization of endothelial precursor cells (EPCs) which can contribute to tumor neovascularization. In contrast, disruption of Ccr2, which encodes CCL2's sole signaling receptor, accelerated tumor development, shortened host survival, and mobilized EPCs. However, pharmacological inhibition of CCR2 phenocopied Ccl2 disruption rather than Ccr2 disruption, suggesting that the Ccr2-/- phenotype is a consequence of unanticipated alterations not linked to intact CCL2/CCR2 signaling. Consistent with this explanation, Ccr2-/- monocytes are more divergent from wild type monocytes than Ccl2-/- monocytes in their expression of genes involved in key developmental and functional pathways. Taken together, our data suggest a tumor-promoting role for CCL2 acting through CCR2 on the tumor microenvironment and support the targeting of this chemokine/receptor pair in breast cancer.
Department of Medical Oncology, Dana-Farber Cancer Institute, and Department of Medicine, Brigham & Women's Hospital, Boston, Massachusetts 02215, United States of America.|Harvard Medical School, Boston, Massachusetts 02115, United States of America.
Xuguang
X
Chen
Department of Medical Oncology, Dana-Farber Cancer Institute, and Department of Medicine, Brigham & Women's Hospital, Boston, Massachusetts 02215, United States of America.|Harvard Medical School, Boston, Massachusetts 02115, United States of America.
Yunyue
Y
Wang
Department of Medical Oncology, Dana-Farber Cancer Institute, and Department of Medicine, Brigham & Women's Hospital, Boston, Massachusetts 02215, United States of America.
David
D
Nelson
Department of Medical Oncology, Dana-Farber Cancer Institute, and Department of Medicine, Brigham & Women's Hospital, Boston, Massachusetts 02215, United States of America.
Sara
S
Tian
Department of Medical Oncology, Dana-Farber Cancer Institute, and Department of Medicine, Brigham & Women's Hospital, Boston, Massachusetts 02215, United States of America.
Erin
E
Mulvey
Department of Medical Oncology, Dana-Farber Cancer Institute, and Department of Medicine, Brigham & Women's Hospital, Boston, Massachusetts 02215, United States of America.
Bhumi
B
Patel
Department of Medical Oncology, Dana-Farber Cancer Institute, and Department of Medicine, Brigham & Women's Hospital, Boston, Massachusetts 02215, United States of America.
Ilaria
I
Conti
ChemoCentryx, Inc., Mountain View, California 94043, United States of America.
Juan
J
Jaen
Department of Medical Oncology, Dana-Farber Cancer Institute, and Department of Medicine, Brigham & Women's Hospital, Boston, Massachusetts 02215, United States of America.|Harvard Medical School, Boston, Massachusetts 02115, United States of America.
Barrett J
BJ
Rollins
D000818:Animals; D045744:Cell Line, Tumor; D018932:Chemokine CCL2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D066026:Endothelial Progenitor Cells / Q000473:pathology; D005260:Female; D017353:Gene Deletion; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D054390:Receptors, CCR2 / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D059016:Tumor Microenvironment
D018932:Chemokine CCL2; D018719:Erb-b2 Receptor Tyrosine Kinases; D054390:Receptors, CCR2; C491768:Ccl2 protein, mouse; C508053:ERBB2 protein, human