Cancer cell CCL5 mediates bone marrow independent angiogenesis in breast cancer

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

Research output: Contribution to journalArticle

17 Scopus citations

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 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.

Original languageEnglish (US)
Pages (from-to)85437-85449
Number of pages13
JournalOncotarget
Volume7
Issue number51
DOIs
StatePublished - 2016

Keywords

  • Angiogenesis
  • Breast cancer
  • CCL5
  • CCR5
  • ShRNAi

ASJC Scopus subject areas

  • Oncology

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