Journal article
CXCL12-γ in Primary Tumors Drives Breast Cancer Metastasis
Oncogene, Vol.34(16), pp.2043-2051
04/16/2015
DOI: 10.1038/onc.2014.157
PMCID: PMC4261050
PMID: 24909174
Abstract
Compelling evidence shows that chemokine 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 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. While 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, 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.
Details
- Title: Subtitle
- CXCL12-γ in Primary Tumors Drives Breast Cancer Metastasis
- Creators
- Paramita Ray - Department of Radiology, University of Michigan Center for Molecular Imaging Biomedical Engineering, University of Michigan Center for Molecular Imaging Department of Internal Medicine, Breast Oncology Program, Comprehensive Cancer Center Microbiology and Immunology, Breast Oncology Program, Comprehensive Cancer CenterAmanda C. Stacer - University of Michigan–Ann ArborJoseph Fenner - University of Michigan–Ann ArborStephen P. Cavnar - University of Michigan–Ann ArborKaille Meguiar - University of Michigan–Ann ArborMartha Brown - University of Michigan–Ann ArborKathryn E. Luker - Department of Radiology, University of Michigan Center for Molecular Imaging Biomedical Engineering, University of Michigan Center for Molecular Imaging Department of Internal Medicine, Breast Oncology Program, Comprehensive Cancer Center Microbiology and Immunology, Breast Oncology Program, Comprehensive Cancer CenterGary D. Luker - University of Michigan–Ann Arbor
- Resource Type
- Journal article
- Publication Details
- Oncogene, Vol.34(16), pp.2043-2051
- DOI
- 10.1038/onc.2014.157
- PMID
- 24909174
- PMCID
- PMC4261050
- ISSN
- 0950-9232
- eISSN
- 1476-5594
- Language
- English
- Date published
- 04/16/2015
- Academic Unit
- Obstetrics and Gynecology
- Record Identifier
- 9984696761602771
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