Cancer cell CCL5 mediates bone marrow independent angiogenesis in breast cancer

Abstract

It has recently been suggested that the chemokine receptor (CCR5) is required for bone marrow (BM) derived endothelial progenitor cell (EPC) mediated angiogenesis. Here we show that suppression of either cancer cell produced CCL5, or host CCR5 leads to distinctive vascular and tumor growth defects in breast cancer. Surprisingly, CCR5 restoration in the BM alone was not sufficient to rescue the wild type phenotype, suggesting that impaired tumor growth associated with inhibiting CCL5/CCR5 is not due to defects in EPC biology. Instead, to promote angiogenesis cancer cell CCL5 may signal directly to endothelium in the tumor-stroma. In support of this hypothesis, we have also shown: (i) that endothelial cell CCR5 levels increases in response to tumor-conditioned media; (ii) that the amount of CCR5+ tumor vasculature correlates with invasive grade; and (iii) that inhibition of CCL5/CCR5 signaling impairs endothelial cell migration, associated with a decrease in activation of mTOR/AKT pathway members. Finally, we show that treatment with CCR5 antagonist results in less vasculature, impaired tumor growth, reduced metastases and improved survival. Taken as a whole, this work demonstrates that directly inhibiting CCR5 expressing vasculature constitutes a novel strategy for inhibiting angiogenesis and blocking metastatic progression in breast cancer.

CC Chemokines in a Tumor: A Review of Pro-Cancer and Anti-Cancer Properties of Receptors CCR5, CCR6, CCR7, CCR8, CCR9, and CCR10 Ligands

“…CCL5 participates in angiogenesis, which is associated with an increase in vascular endothelial growth factor (VEGF) expression in cancer cells and vascular endothelial cells via the activation of CCR1 and CCR5 [ 99 , 100 , 101 , 102 ]. CCL5 may cause differentiation of cancer stem cells into endothelial cells as observed in the ovarian cancer model [ 103 ].…”

The effect of CCL5 on the immune cells infiltration and the prognosis of patients with kidney renal clear cell carcinoma

“…It can also indirectly promote tumor cell proliferation by recruiting macrophages, fibroblasts, T cells, etc 37 , 38 . At the same time, CCL5 can promote angiogenesis through promoting endothelial cell migration, neovascularization, and the secretion of vascular endothelial growth factor (VEGF) 39 - 41 . In addition, it plays an important role in tumor cell migration through upregulating MMP2 and MMP9 expression or activating integrin 42 - 44 .…”

G Protein-Coupled Receptors at the Crossroad between Physiologic and Pathologic Angiogenesis: Old Paradigms and Emerging Concepts

“…Altogether these studies suggest that CCL5/CCR5 signaling regulates angiogenic responses in cancer by modulating certain miRNAs, nevertheless the stimulatory actions mediated by CCR5 may also rely on the direct regulation of the HIF-1α/VEGF transduction pathway [ 163 ]. Recently, it has also been established that the suppression of cancer cell-produced CCL5 or host CCR5 could result in defective breast tumor vascularization and growth [ 65 ]. For instance, the impairment in CCL5/CCR5 signaling abrogated angiogenesis by targeting the interactions between tumor and ECs, rather than halting the bone marrow derived activation of EPCs.…”

“…For instance, the impairment in CCL5/CCR5 signaling abrogated angiogenesis by targeting the interactions between tumor and ECs, rather than halting the bone marrow derived activation of EPCs. These observations indicate that the abrogation of CCR5-mediated action may block tumor vascularization by hijacking microenvironmental communications, rather than altering EPC biology [ 65 ].…”