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Cancer cell CCL5 mediates bone marrow independent angiogenesis in breast cancer

2016; Impact Journals LLC; Volume: 7; Issue: 51 Linguagem: Inglês

10.18632/oncotarget.13387

1949-2553

Michael Sax, Christin Gasch, Vineel Rag Athota, Ruth Freeman, Parisa Rasighaemi, David Elton Westcott, Christopher J. Day, Iva Nikolić, Benjamin Elsworth, Ming Wei, Kelly L. Rogers, Alexander Swarbrick, Vivek Mittal, Normand Pouliot, Albert S. Mellick,

Cancer, Hypoxia, and Metabolism

// Michael John Sax 1 , Christin Gasch 2 , Vineel Rag Athota 2 , Ruth Freeman 1 , Parisa Rasighaemi 2 , David Elton Westcott 11 , Christopher John Day 3 , Iva Nikolic 4, 5 , Benjamin Elsworth 4, 5 , Ming Wei 1 , Kelly Rogers 6 , Alexander Swarbrick 4, 5 , Vivek Mittal 7 , Normand Pouliot 8, 9, * , Albert Sleiman Mellick 1, 2, 10, 11, 12, * 1 School of Medical Science, Griffith University, Gold Coast, QLD, Australia 2 School of Medicine, Deakin University, Waurn Ponds, Victoria, Australia 3 Glycomics Institute, Griffith University, Gold Coast, QLD, Australia 4 Kinghorn Cancer Centre & Cancer Research Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia 5 St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Kensington NSW, Australia 6 Centre for Dynamic Imaging, Walter and Eliza Hall Institute for Medical Research, Parkville Victoria, Australia 7 Cardiothoracic Surgery and Neuberger Berman Lung Cancer Centre, Weill Cornell Medical College, New York, NY, USA 8 Matrix Microenvironment & Metastasis Laboratory, Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia 9 School of Cancer Medicine, La Trobe University, Heidelberg, Victoria, Australia 10 Faculty of Medicine, University of New South Wales, NSW, Australia 11 School of Medicine, Western Sydney University, Campbelltown NSW, Australia 12 Translational Oncology Unit, Ingham Institute for Applied Medical Research, Liverpool NSW, Australia * Normand Pouliot and Albert Sleiman Mellick share senior authorship Correspondence to: Albert Sleiman Mellick, email: a.mellick@unsw.edu.au Keywords: angiogenesis, shRNAi, breast cancer, CCL5, CCR5 Received: August 24, 2016 Accepted: October 27, 2016 Published: November 16, 2016 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.