title: Endothelial CXCR7 regulates breast cancer metastasis.
abstract: Atypical chemokine receptor CXCR7 (ACKR3) functions as a scavenger receptor for chemokine CXCL12, a molecule that promotes multiple steps in tumor growth and metastasis in breast cancer and multiple other malignancies. Although normal vascular endothelium expresses low levels of CXCR7, marked upregulation of CXCR7 occurs in tumor vasculature in breast cancer and other tumors. To investigate effects of endothelial CXCR7 in breast cancer, we conditionally deleted this receptor from vascular endothelium of adult mice, generating CXCR7(ΔEND/ΔEND) animals. CXCR7(ΔEND/ΔEND) mice appeared phenotypically normal, although these animals exhibited a modest 35±3% increase in plasma CXCL12 as compared with control. Using two different syngeneic, orthotopic tumor implant models of breast cancer, we discovered that CXCR7(ΔEND/ΔEND) mice had significantly greater local recurrence of cancer following resection, elevated numbers of circulating tumor cells and more spontaneous metastases. CXCR7(ΔEND/ΔEND) mice also showed greater experimental metastases following intracardiac injection of cancer cells. These results establish that endothelial CXCR7 limits breast cancer metastasis at multiple steps in the metastatic cascade, advancing understanding of CXCL12 pathways in tumor environments and informing ongoing drug development targeting CXCR7 in cancer.
authors.affiliation: University of Michigan Center for Molecular Imaging, Department of Radiology, University of Michigan Medical School and College of Engineering, Ann Arbor, MI, USA.
authors.forename: A C
authors.initials: AC
authors.lastname: Stacer
authors.affiliation: University of Michigan Center for Molecular Imaging, Department of Radiology, University of Michigan Medical School and College of Engineering, Ann Arbor, MI, USA.
authors.forename: J
authors.initials: J
authors.lastname: Fenner
authors.affiliation: Department of Biomedical Engineering, University of Michigan Medical School and College of Engineering, Ann Arbor, MI, USA.
authors.forename: S P
authors.initials: SP
authors.lastname: Cavnar
authors.affiliation: University of Michigan Center for Molecular Imaging, Department of Radiology, University of Michigan Medical School and College of Engineering, Ann Arbor, MI, USA.
authors.forename: A
authors.initials: A
authors.lastname: Xiao
authors.affiliation: Department of Radiation Oncology, University of Michigan Medical School and College of Engineering, Ann Arbor, MI, USA.
authors.forename: S
authors.initials: S
authors.lastname: Zhao
authors.affiliation: Depatment of Chemical Engineering, University of Michigan Medical School and College of Engineering, Ann Arbor, MI, USA.
authors.forename: S L
authors.initials: SL
authors.lastname: Chang
authors.affiliation: University of Michigan Center for Molecular Imaging, Department of Radiology, University of Michigan Medical School and College of Engineering, Ann Arbor, MI, USA.
authors.forename: A
authors.initials: A
authors.lastname: Salomonnson
authors.affiliation: University of Michigan Center for Molecular Imaging, Department of Radiology, University of Michigan Medical School and College of Engineering, Ann Arbor, MI, USA.
authors.forename: K E
authors.initials: KE
authors.lastname: Luker
authors.affiliation: University of Michigan Center for Molecular Imaging, Department of Radiology, University of Michigan Medical School and College of Engineering, Ann Arbor, MI, USA.|Department of Biomedical Engineering, University of Michigan Medical School and College of Engineering, Ann Arbor, MI, USA.|Department of Microbiology and Immunology, University of Michigan Medical School and College of Engineering, Ann Arbor, MI, USA.
authors.forename: G D
authors.initials: GD
authors.lastname: Luker
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology*; D045744:Cell Line, Tumor; D004730:Endothelium, Vascular / Q000378:metabolism*; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009362:Neoplasm Metastasis; D054387:Receptors, CXCR / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D059016:Tumor Microenvironment / Q000235:genetics
chemical_list: C501897:Cmkor1 protein, mouse; D054387:Receptors, CXCR