Cancer cell CCL5 mediates bone marrow independent angiogenesis in breast cancer
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Michael John Sax1, Christin Gasch2, Vineel Rag Athota2, Ruth Freeman1, Parisa Rasighaemi2, David Elton Westcott11, Christopher John Day3, Iva Nikolic4,5, Benjamin Elsworth4,5, Ming Wei1, Kelly Rogers6, Alexander Swarbrick4,5, Vivek Mittal7, Normand Pouliot8,9,*, Albert Sleiman Mellick1,2,10,11,12,*
1School of Medical Science, Griffith University, Gold Coast, QLD, Australia
2School of Medicine, Deakin University, Waurn Ponds, Victoria, Australia
3Glycomics Institute, Griffith University, Gold Coast, QLD, Australia
4Kinghorn Cancer Centre & Cancer Research Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
5St Vincent’s Clinical School, Faculty of Medicine, University of New South Wales, Kensington NSW, Australia
6Centre for Dynamic Imaging, Walter and Eliza Hall Institute for Medical Research, Parkville Victoria, Australia
7Cardiothoracic Surgery and Neuberger Berman Lung Cancer Centre, Weill Cornell Medical College, New York, NY, USA
8Matrix Microenvironment & Metastasis Laboratory, Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia
9School of Cancer Medicine, La Trobe University, Heidelberg, Victoria, Australia
10Faculty of Medicine, University of New South Wales, NSW, Australia
11School of Medicine, Western Sydney University, Campbelltown NSW, Australia
12Translational Oncology Unit, Ingham Institute for Applied Medical Research, Liverpool NSW, Australia
*Normand Pouliot and Albert Sleiman Mellick share senior authorship
Albert Sleiman Mellick, email: [email protected]
Keywords: angiogenesis, shRNAi, breast cancer, CCL5, CCR5
Received: August 24, 2016 Accepted: October 27, 2016 Published: November 16, 2016
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.
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