title: CXCL12-γ in primary tumors drives breast cancer metastasis.
abstract: Compelling evidence shows that chemokine C-X-C motif chemokine ligand 12 (CXCL12) drives metastasis in multiple malignancies. Similar to other key cytokines in cancer, CXCL12 exists as several isoforms with distinct biophysical properties that may alter signaling and functional outputs. However, effects of CXCL12 isoforms in cancer remain unknown. CXCL12-α, -β and -γ showed cell-type-specific differences in activating signaling through G protein-dependent pathways in cell-based assays, while CXCL12-γ had greatest effects on recruitment of the adapter protein β-arrestin 2. CXCL12-β and -γ also stimulated endothelial tube formation to a greater extent than CXCL12-α. To investigate the effects of CXCL12 isoforms on tumor growth and metastasis, we used a mouse xenograft model of metastatic human breast cancer combining CXCR4+ breast cancer cells and mammary fibroblasts secreting an isoform of CXCL12. Altough all CXCL12 isoforms produced comparable growth of mammary tumors, CXCL12-γ significantly increased metastasis to bone marrow and other sites. Breast cancer cells originating from tumors with CXCL12-γ fibroblasts upregulated RANKL (receptor activator of nuclear factor-κB ligand), contributing to bone marrow tropism of metastatic cancer cells. CXCL12-γ was expressed in metastatic tissues in mice, and we also detected CXCL12-γ in malignant pleural effusions from patients with breast cancer. In our mouse model, mammary fibroblasts disseminated to sites of breast cancer metastases, providing another mechanism to increase levels of CXCL12 in metastatic environments. These studies identify CXCL12-γ as a potent pro-metastatic molecule with important implications for cancer biology and effective therapeutic targeting of CXCL12 pathways.
authors.affiliation: Center for Molecular Imaging, Department of Radiology, University of Michigan, Ann Arbor, MI, USA.
authors.forename: P
authors.initials: P
authors.lastname: Ray
authors.affiliation: Center for Molecular Imaging, Department of Radiology, University of Michigan, Ann Arbor, MI, USA.
authors.forename: A C
authors.initials: AC
authors.lastname: Stacer
authors.affiliation: Center for Molecular Imaging, Department of Radiology, University of Michigan, Ann Arbor, MI, USA.
authors.forename: J
authors.initials: J
authors.lastname: Fenner
authors.affiliation: Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA.
authors.forename: S P
authors.initials: SP
authors.lastname: Cavnar
authors.affiliation: Center for Molecular Imaging, Department of Radiology, University of Michigan, Ann Arbor, MI, USA.
authors.forename: K
authors.initials: K
authors.lastname: Meguiar
authors.affiliation: Breast Oncology Program, Comprehensive Cancer Center, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
authors.forename: M
authors.initials: M
authors.lastname: Brown
authors.affiliation: Center for Molecular Imaging, Department of Radiology, University of Michigan, Ann Arbor, MI, USA.
authors.forename: K E
authors.initials: KE
authors.lastname: Luker
authors.affiliation: 1] Center for Molecular Imaging, Department of Radiology, University of Michigan, Ann Arbor, MI, USA [2] Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA [3] Breast Oncology Program, Comprehensive Cancer Center, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA [4] Department of Microbiology and Immunology, University of Michigan Center, Ann Arbor, MI, USA 
authors.forename: G D
authors.initials: GD
authors.lastname: Luker
mesh_terms: D000818:Animals; D019390:Arrestins / Q000378:metabolism; D001859:Bone Neoplasms / Q000235:genetics / Q000556:secondary*; D001943:Breast Neoplasms / Q000473:pathology*; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000473:pathology; D006801:Humans; D051379:Mice; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D053245:RANK Ligand / Q000096:biosynthesis; D019718:Receptors, CXCR4 / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins
chemical_list: C000605254:ARRB2 protein, human; C000605258:Arrb2 protein, mouse; D019390:Arrestins; C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D020033:Protein Isoforms; D053245:RANK Ligand; D019718:Receptors, CXCR4; C505688:TNFSF11 protein, human; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins