CCR2 signaling in breast carcinoma cells promotes tumor growth and invasion by promoting CCL2 and suppressing CD154 effects on the angiogenic and immune microenvironments

Abstract

Breast cancer is the second leading cause of cancer related deaths for women, due mainly to metastatic disease. Invasive tumors exhibit aberrations in recruitment and activity of immune cells, including decreased cytotoxic T cells. Restoring the levels and activity of cytotoxic T cells is a promising anti-cancer strategy; but its success is tumor type-dependent. The mechanisms that coordinate recruitment and activity of immune cells and other stromal cells in breast cancer remain poorly understood. Using the MMTV-PyVmT/FVB mammary tumor model, we demonstrate a novel role for CCL2/CCR2 chemokine signaling in tumor progression by altering the microenvironment. Selective targeting of CCR2 in the PyVmT mammary epithelium inhibited tumor growth and invasion, elevated CD8+ T cells, decreased M2 macrophages and decreased angiogenesis. Co-culture models demonstrated these stromal cell responses were mediated by tumor derived CCL2 and CCR2-mediated suppression of the T cell activating cytokine, CD154. Co-culture analysis indicated that CCR2-induced stromal reactivity was important for tumor cell proliferation and invasion. In breast tumor tissues, CD154 expression inversely correlated with CCR2 expression and correlated with relapse free survival. Targeting the CCL2/CCR2 signaling pathway may reprogram the immune angiogenic and microenvironments and enhance effectiveness of targeted and immuno-therapies.Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

M2 macrophage-induced lncRNA PCAT6 facilitates tumorigenesis and angiogenesis of triple-negative breast cancer through modulation of VEGFR2

“…Zhu et al pointed out that immune cell recruitment is reduced, while M2-like macrophages are increased in metastatic BC tumors 16 . Brummer et al have revealed that selective targeting of CCR2 impaired BC tumor growth and invasion as well as decreased M2 macrophages-induced angiogenesis 17 . Chen et al revealed that activated M2 macrophages are strongly associated with survival for both Asian and Western patients with BC 18 .…”

Targeting tumor cell-derived CCL2 as a strategy to overcome bevacizumab resistance in ETV5+ colorectal cancer

“…CCL2 was identi ed as another proangiogenic factor induced by ETV5 in CRC. CCL2/CCR2 chemokine signaling was proved to promote breast cancer progression by induced angiogenesis [20]. By ELISA assay, we found that attenuation of VEGFA could not affect ETV5-mediated CCL2 secretion, and anti-CCL2 treatment also did not have in uence on ETV5-mediated VEGFA secretion in CRC cells.…”

“…Similarly, our previous study showed that ETV5 facilitated CRC angiogenesis via PDGF-BB/Src/STAT3/VEGFA signaling pathway [19]. Besides, more and more studies indicated that chemokine signaling played critical roles in tumor angiogenesis, such as CCL2/CCR2 signaling and CXCL11/CXCR7 signaling [20,21]. ETV5 was also reported to regulate chemokines expression of sertoli cell in mouse, such as Ccl7, Ccl9, Ccl12.…”

The Multifaceted Nature of Tumor Microenvironment in Breast Carcinomas

“…Other factors contribute to increase the breast angiogenic microenvironment. For instance, recent studies showed that CCL2/CCR2 signaling in breast cancer cells regulates tumor growth and invasion by promoting angiogenesis through the recruitment and branching of endothelial cells, recruiting and polarizing macrophages to M2 phenotype, and suppressing cytotoxic T-cell activity [156]. Kim et al [157] analyzed both the expression levels of Notch1, a signaling pathway involved in cell proliferation and angiogenesis, and microRNAs-34a in 114 TNBC samples and reported better OS in patients presenting low EC Notch1 (Notch1 microvascular density to CD34 microvascular density ratio) than those with a high ratio, and a significant correlation between high microRNAs-34a levels, decreased vessel formation (low EC Notch1 levels) and higher survival benefit in a lymph-node-positive group [157].…”