CCL2/CCR2 Regulates the Tumor Microenvironment in HER-2/neu-Driven Mammary Carcinomas in Mice

• DOI: 10.1371/journal.pone.0165595
• Publication Date: 2016-11-07T18:28:02Z
• Authors: Xuguang Chen; Yunyue Wang; David Nelson; Sara Tian; Erin Mulvey; Bhumi Patel; Ilaria Conti; Juan Jaen; Barrett J. Rollins
• Keywords: 0301 basic medicine; Physiology; Receptor, ErbB-2; Cancer Treatment; Monocytes; White Blood Cells; Mice; Animal Cells; Bone Marrow; Immune Physiology; Breast Tumors; Medicine and Health Sciences; Tumor Microenvironment; Enzyme-Linked Immunoassays; Chemokine CCL2; Endothelial Progenitor Cells; Mammals; Q; R; Animal Models; 3. Good health; Oncology; Vertebrates; Medicine; Female; Cellular Types; Research Article; Receptors, CCR2; Immune Cells; Science; Immunology; 610; Mouse Models; Rodents; Carcinomas; 03 medical and health sciences; Model Organisms; Cell Line, Tumor; Breast Cancer; Animals; Humans; Immunoassays; Blood Cells; Organisms; Biology and Life Sciences; Cancers and Neoplasms; Mammary Neoplasms, Experimental; Cell Biology; Immune System; Amniotes; Immunologic Techniques; Gene Deletion

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.