posters International Association for Breast Cancer Research 2014

C-C chemokine receptor 5 (CCR5) is required for tumour angiogenesis (#90)

Prue N. Plummer 1 , Michael J. Sax 2 , Christin Gasch 1 , Alexander Swarbrick 3 , Vivek Mittal 4 , Albert Mellick 1
  1. School of Medicine, Deakin University , Geelong Waurn Ponds Campus, VIC, Australia
  2. Griffith University, Southport, QLD, Australia
  3. Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
  4. Weill Cornell Medical College, New York, NY, USA

The chemokine ligand RANTES/CCL5 and its receptor (CCR5) have been linked with malignancy in breast cancer. Recent studies have also implied a role for the CCL5/CCR5 axis in endothelial progenitor cell (EPC) mediated breast cancer neovascularization and spread. Bone marrow (BM)-derived EPCs regulate the angiogenic switch via paracrine secretion of proangiogenic growth factors, and by direct luminal incorporation into sprouting nascent vessels1,2. Here we show that specific suppression of tumour cell produced CCL5 in vivo, leads to distinctive vascular and tumour growth defects. However, loss of BM CCR5 does not result in significant tumour growth defects, and restoration of CCR5 in the BM is not able to overcome loss of CCR5 in the non-BM compartment of the tumour stroma. This suggests that the tumour defects associated with CCR5 ablation are due to defects in pre-existing vasculature, not EPCs. In support of a role for CCR5 in establishment of mature tumour vasculature, we further demonstrate that CCR5 is up-regulated in endothelial cells in response to tumour-conditioned medium; and that specific suppression of CCR5 in endothelial cells leads to significant angiogenic defects. We have further observed a significant correlation between CCR5 vascular expression and a more aggressive breast cancer type. This work demonstrates that the CCL5/CCR5 axis is important in tumour angiogenesis driven by pre-existing vasculature and that directly targeting CCR5 expressing vasculature may constitute a novel strategy for inhibiting tumour angiogenesis in breast cancer.

  1. Plummer PN, Freeman R, Taft R et al., MicroRNAs regulate tumor angiogenesis modulated by endothelial progenitor cells. Cancer Research. 2013;73:341-52.
  2. Mellick AS, Plummer PN, Nolan DJ et al., Using the Transcription Factor Inhibitor of DNA Binding 1 to Selectively Target Endothelial Progenitor Cells Offers Novel Strategies to Inhibit Tumor Angiogenesis and Growth. Cancer Research. 2010;70:7273-82.