Poster Presentation 27th Lorne Cancer Conference 2015

C-C chemokine receptor 5 (CCR5) is required for tumor angiogenesis. (#220)

Michael J Sax 1 , Prue N Plummer 2 , Christin Gasch 2 , Christopher J Day 1 , Ruth Freeman 1 , Alexander Swarbrick 3 , Ming Wei 1 , Vivek Mittal 4 , Albert S Mellick 1 2
  1. Griffith University, Southport, QLD, Australia
  2. School of Medicine, Deakin University, Waurn Ponds, VIC, Australia
  3. Garvan Institute of Medical Research, Sydney, NSW, Australia
  4. Lung Cancer Centre, Weill Cornell Medical College, New York, United States

The chemokine ligand RANTES/CCL5 and its cognate receptor (CCR5) have a long history in T-cell biology. However, despite increasing body of literature suggesting association between CCL5 and cancer malignancy little is understood of the mechanism underlying CCL5/RANTES signalling in cancer cell biology. In the work presented in this paper, we use stable and specific suppression of the chemokine ligand for CCR1 and CCR5, CCL5 in two different immune competent breast tumour models, to show for the first time that suppression of tumour-CCL5, does lead to distinctive tumour growth, and BM-associated angiogenesis defects. In order to investigate the mechanism, we next implanted mice that are homozygous null for CCR1 and CCR5, with breast tumours. This revealed growth and vascular defects in tumours grown in CCR5null mice, as well as impaired endothelial progenitor cell (EPC)1,2 biology. To determine the contribution of the BM compartment of the tumour stroma to CCL5 mediated angiogenesis, we transplanted WT animals with CCR1 and CCR5-null BM. The results suggested that while tumour CCL5 signaling is linked to BM-mediated tumour angiogenesis, CCR5 expression by EPCs was not enough to compensate for lack of CCR5 in the non-BM-compartment of the tumour-stroma. Thus, paracrine signalling of tumour CCL5 to pre-existing vasculature is likely to be the major driver of CCL5/CCR5 mediated angiogenesis and neovascularisation. We further show that CCR5 expression correlates with adverse pathologies in human breast cancer, with significantly higher levels of CCR5+ vessels in invasive Her2+, ER+ and TNBC tumours, compared with more restricted DCIS tumours. Finally, we have demonstrated, through specific suppression of CCR5, that endothelial cell CCR5 plays a direct role in vascular biology; with significant effects on tube formation and wound healing. The work presented in our paper (in review, Cancer Research), linking CCL5 with EPCs and tumour vasculature, provides a complementary explanation for the reduced metastatic involvement previously reported by Weinberg and others following CCL5/CCR5 suppression. It also suggests that modulating EPC and tumour vascular chemokines, has the potential to provide a multi-prong approach to treating cancer, by blocking tumour spread, as well as, by suppressing the angiogenic switch at the site of secondary metastases

  1. Plummer PN, Freeman R, Taft RJ, Vider J, Sax M, Umer BA, Gao D, Johns C, Mattick JS, Wilton SD, Ferro V, McMillan NA, Swarbrick A, Mittal V, Mellick AS. MicroRNAs regulate tumor angiogenesis modulated by endothelial progenitor cells. Cancer Res. 2013 Jan 1;73(1):341-52.
  2. Mellick AS, Plummer PN, Nolan DJ, Gao D, Bambino K, Hahn M, Catena R, Turner V, McDonnell K, Benezra R, Brink R, Swarbrick A, Mittal V. 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 Res. 2010 Sep 15;70(18):7273-82.