title: Cancer cell CCL5 mediates bone marrow independent angiogenesis in breast cancer.
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.
authors.affiliation: School of Medical Science, Griffith University, Gold Coast, QLD, Australia.
authors.forename: Michael John
authors.initials: MJ
authors.lastname: Sax
authors.affiliation: School of Medicine, Deakin University, Waurn Ponds, Victoria, Australia.
authors.forename: Christin
authors.initials: C
authors.lastname: Gasch
authors.affiliation: School of Medicine, Deakin University, Waurn Ponds, Victoria, Australia.
authors.forename: Vineel Rag
authors.initials: VR
authors.lastname: Athota
authors.affiliation: School of Medical Science, Griffith University, Gold Coast, QLD, Australia.
authors.forename: Ruth
authors.initials: R
authors.lastname: Freeman
authors.affiliation: School of Medicine, Deakin University, Waurn Ponds, Victoria, Australia.
authors.forename: Parisa
authors.initials: P
authors.lastname: Rasighaemi
authors.affiliation: School of Medicine, Western Sydney University, Campbelltown NSW, Australia.
authors.forename: David Elton
authors.initials: DE
authors.lastname: Westcott
authors.affiliation: Glycomics Institute, Griffith University, Gold Coast, QLD, Australia.
authors.forename: Christopher John
authors.initials: CJ
authors.lastname: Day
authors.affiliation: Kinghorn Cancer Centre & Cancer Research Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.|St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Kensington NSW, Australia.
authors.forename: Iva
authors.initials: I
authors.lastname: Nikolic
authors.affiliation: Kinghorn Cancer Centre & Cancer Research Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.|St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Kensington NSW, Australia.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Elsworth
authors.affiliation: School of Medical Science, Griffith University, Gold Coast, QLD, Australia.
authors.forename: Ming
authors.initials: M
authors.lastname: Wei
authors.affiliation: Centre for Dynamic Imaging, Walter and Eliza Hall Institute for Medical Research, Parkville Victoria, Australia.
authors.forename: Kelly
authors.initials: K
authors.lastname: Rogers
authors.affiliation: Kinghorn Cancer Centre & Cancer Research Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.|St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Kensington NSW, Australia.
authors.forename: Alexander
authors.initials: A
authors.lastname: Swarbrick
authors.affiliation: Cardiothoracic Surgery and Neuberger Berman Lung Cancer Centre, Weill Cornell Medical College, New York, NY, USA.
authors.forename: Vivek
authors.initials: V
authors.lastname: Mittal
authors.affiliation: Matrix Microenvironment & Metastasis Laboratory, Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia.|School of Cancer Medicine, La Trobe University, Heidelberg, Victoria, Australia.
authors.forename: Normand
authors.initials: N
authors.lastname: Pouliot
authors.affiliation: School of Medical Science, Griffith University, Gold Coast, QLD, Australia.|School of Medicine, Deakin University, Waurn Ponds, Victoria, Australia.|Faculty of Medicine, University of New South Wales, NSW, Australia.|School of Medicine, Western Sydney University, Campbelltown NSW, Australia.|Translational Oncology Unit, Ingham Institute for Applied Medical Research, Liverpool NSW, Australia.
authors.forename: Albert Sleiman
authors.initials: AS
authors.lastname: Mellick
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D001943:Breast Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D065100:CCR5 Receptor Antagonists / Q000494:pharmacology; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D018946:Chemokine CCL5 / Q000235:genetics / Q000378:metabolism*; D017077:Culture Media, Conditioned / Q000378:metabolism; D003510:Cyclohexanes / Q000494:pharmacology; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D000077592:Maraviroc; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D060787:Neoplasm Grading; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic; D019899:Paracrine Communication; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019713:Receptors, CCR5 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D013997:Time Factors; D014230:Triazoles / Q000494:pharmacology; D047368:Tumor Burden; D059016:Tumor Microenvironment
chemical_list: D020533:Angiogenesis Inhibitors; C483024:CCL5 protein, human; D065100:CCR5 Receptor Antagonists; C584933:CCR5 protein, human; C000592874:CCR5 protein, mouse; C503460:Ccl5 protein, mouse; D018946:Chemokine CCL5; D017077:Culture Media, Conditioned; D003510:Cyclohexanes; D019713:Receptors, CCR5; D014230:Triazoles; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D000077592:Maraviroc
keywords: CCL5; CCR5; angiogenesis; breast cancer; shRNAi