TY - JOUR
T1 - Cancer cell CCL5 mediates bone marrow independent angiogenesis in breast cancer
AU - Sax, Michael John
AU - Gasch, Christin
AU - Athota, Vineel Rag
AU - Freeman, Ruth
AU - Rasighaemi, Parisa
AU - Westcott, David Elton
AU - Day, Christopher John
AU - Nikolic, Iva
AU - Elsworth, Benjamin
AU - Wei, Ming
AU - Rogers, Kelly
AU - Swarbrick, Alexander
AU - Mittal, Vivek
AU - Pouliot, Normand
AU - Mellick, Albert Sleiman
PY - 2016
Y1 - 2016
N2 - 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 tumorconditioned 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.
AB - 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 tumorconditioned 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.
KW - bone marrow
KW - breast
KW - cancer
KW - neovascularization
UR - http://handle.westernsydney.edu.au:8081/1959.7/uws:38362
U2 - 10.18632/oncotarget.13387
DO - 10.18632/oncotarget.13387
M3 - Article
SN - 1949-2553
VL - 7
SP - 85437
EP - 85449
JO - Oncotarget
JF - Oncotarget
IS - 51
ER -