PMID- 24909174
OWN - NLM
STAT- MEDLINE
DCOM- 20150727
LR  - 20211021
IS  - 1476-5594 (Electronic)
IS  - 0950-9232 (Print)
IS  - 0950-9232 (Linking)
VI  - 34
IP  - 16
DP  - 2015 Apr 16
TI  - CXCL12-gamma in primary tumors drives breast cancer metastasis.
PG  - 2043-51
LID - 10.1038/onc.2014.157 [doi]
AB  - 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-alpha, -beta and -gamma showed cell-type-specific 
      differences in activating signaling through G protein-dependent pathways in 
      cell-based assays, while CXCL12-gamma had greatest effects on recruitment of the 
      adapter protein beta-arrestin 2. CXCL12-beta and -gamma also stimulated endothelial tube 
      formation to a greater extent than CXCL12-alpha. 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-gamma significantly increased metastasis 
      to bone marrow and other sites. Breast cancer cells originating from tumors with 
      CXCL12-gamma fibroblasts upregulated RANKL (receptor activator of nuclear factor-kappaB 
      ligand), contributing to bone marrow tropism of metastatic cancer cells. CXCL12-gamma 
      was expressed in metastatic tissues in mice, and we also detected CXCL12-gamma 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-gamma as a potent pro-metastatic molecule with important 
      implications for cancer biology and effective therapeutic targeting of CXCL12 
      pathways.
FAU - Ray, P
AU  - Ray P
AD  - Center for Molecular Imaging, Department of Radiology, University of 
      Michigan, Ann Arbor, MI, USA.
FAU - Stacer, A C
AU  - Stacer AC
AD  - Center for Molecular Imaging, Department of Radiology, University of 
      Michigan, Ann Arbor, MI, USA.
FAU - Fenner, J
AU  - Fenner J
AD  - Center for Molecular Imaging, Department of Radiology, University of 
      Michigan, Ann Arbor, MI, USA.
FAU - Cavnar, S P
AU  - Cavnar SP
AD  - Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA.
FAU - Meguiar, K
AU  - Meguiar K
AD  - Center for Molecular Imaging, Department of Radiology, University of 
      Michigan, Ann Arbor, MI, USA.
FAU - Brown, M
AU  - Brown M
AD  - Breast Oncology Program, Comprehensive Cancer Center, Department of Internal 
      Medicine, University of Michigan, Ann Arbor, MI, USA.
FAU - Luker, K E
AU  - Luker KE
AD  - Center for Molecular Imaging, Department of Radiology, University of 
      Michigan, Ann Arbor, MI, USA.
FAU - Luker, G D
AU  - Luker GD
AD  - 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 
LA  - eng
GR  - R01CA136553/CA/NCI NIH HHS/United States
GR  - R01CA136829/CA/NCI NIH HHS/United States
GR  - R01 CA136829/CA/NCI NIH HHS/United States
GR  - R01CA142750/CA/NCI NIH HHS/United States
GR  - R01 CA142750/CA/NCI NIH HHS/United States
GR  - R01 CA136553/CA/NCI NIH HHS/United States
GR  - P50CA093990/CA/NCI NIH HHS/United States
GR  - P50 CA093990/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20140609
PL  - England
TA  - Oncogene
JT  - Oncogene
JID - 8711562
RN  - 0 (ARRB2 protein, human)
RN  - 0 (Arrb2 protein, mouse)
RN  - 0 (Arrestins)
RN  - 0 (CXCL12 protein, human)
RN  - 0 (CXCR4 protein, human)
RN  - 0 (Chemokine CXCL12)
RN  - 0 (Protein Isoforms)
RN  - 0 (RANK Ligand)
RN  - 0 (Receptors, CXCR4)
RN  - 0 (TNFSF11 protein, human)
RN  - 0 (beta-Arrestin 2)
RN  - 0 (beta-Arrestins)
SB  - IM
MH  - Animals
MH  - Arrestins/metabolism
MH  - Bone Neoplasms/genetics/*secondary
MH  - Breast Neoplasms/*pathology
MH  - Cells, Cultured
MH  - Chemokine CXCL12/genetics/*metabolism/pharmacology
MH  - Female
MH  - Gene Expression Regulation, Neoplastic
MH  - Human Umbilical Vein Endothelial Cells/drug effects/pathology
MH  - Humans
MH  - Mice
MH  - Protein Isoforms/genetics/metabolism
MH  - RANK Ligand/biosynthesis
MH  - Receptors, CXCR4/metabolism
MH  - Xenograft Model Antitumor Assays
MH  - beta-Arrestin 2
MH  - beta-Arrestins
PMC - PMC4261050
MID - NIHMS592146
COIS- Conflict of Interest: The authors declare no conflicts of interest relevant to 
      this manuscript.
EDAT- 2014/06/10 06:00
MHDA- 2015/07/28 06:00
PMCR- 2015/10/16
CRDT- 2014/06/10 06:00
PHST- 2013/12/26 00:00 [received]
PHST- 2014/04/04 00:00 [revised]
PHST- 2014/05/01 00:00 [accepted]
PHST- 2014/06/10 06:00 [entrez]
PHST- 2014/06/10 06:00 [pubmed]
PHST- 2015/07/28 06:00 [medline]
PHST- 2015/10/16 00:00 [pmc-release]
AID - onc2014157 [pii]
AID - 10.1038/onc.2014.157 [doi]
PST - ppublish
SO  - Oncogene. 2015 Apr 16;34(16):2043-51. doi: 10.1038/onc.2014.157. Epub 2014 Jun 9.