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Tumor-extrinsic discoidin domain receptor 1 promotes mammary tumor growth by regulating adipose stromal interleukin 6 production in mice.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2018 Feb 23; Vol. 293 (8), pp. 2841-2849. Date of Electronic Publication: 2018 Jan 03. - Publication Year :
- 2018
-
Abstract
- Discoidin domain receptor 1 (DDR1) is a collagen receptor that mediates cell communication with the extracellular matrix (ECM). Aberrant expression and activity of DDR1 in tumor cells are known to promote tumor growth. Although elevated DDR1 levels in the stroma of breast tumors are associated with poor patient outcome, a causal role for tumor-extrinsic DDR1 in cancer promotion remains unclear. Here we report that murine mammary tumor cells transplanted to syngeneic recipient mice in which Ddr1 has been knocked out (KO) grow less robustly than in WT mice. We also found that the tumor-associated stroma in Ddr1- KO mice exhibits reduced collagen deposition compared with the WT controls, supporting a role for stromal DDR1 in ECM remodeling of the tumor microenvironment. Furthermore, the stromal-vascular fraction (SVF) of Ddr1 knockout adipose tissue, which contains committed adipose stem/progenitor cells and preadipocytes, was impaired in its ability to stimulate tumor cell migration and invasion. Cytokine array-based screening identified interleukin 6 (IL-6) as a cytokine secreted by the SVF in a DDR1-dependent manner. SVF-produced IL-6 is important for SVF-stimulated tumor cell invasion in vitro , and, using antibody-based neutralization, we show that tumor promotion by IL-6 in vivo requires DDR1. In conclusion, our work demonstrates a previously unrecognized function of DDR1 in promoting tumor growth.<br /> (© 2018 by The American Society for Biochemistry and Molecular Biology, Inc.)
- Subjects :
- Adipose Tissue drug effects
Adipose Tissue immunology
Adipose Tissue pathology
Animals
Antibodies, Neutralizing pharmacology
Breast Neoplasms drug therapy
Breast Neoplasms immunology
Breast Neoplasms pathology
Cell Line, Tumor
Cell Movement drug effects
Cell Proliferation drug effects
Collagen metabolism
Discoidin Domain Receptor 1 genetics
Female
Humans
Mice
Mice, Inbred C57BL
Mice, Knockout
Neoplasm Invasiveness immunology
Neoplasm Invasiveness pathology
Neoplasm Invasiveness prevention & control
Neoplasm Proteins genetics
Neoplasm Proteins metabolism
Neoplasm Transplantation
Stromal Cells drug effects
Stromal Cells immunology
Stromal Cells pathology
Transplantation, Isogeneic
Tumor Burden drug effects
Tumor Cells, Cultured
Tumor Microenvironment drug effects
Adipose Tissue metabolism
Breast Neoplasms metabolism
Discoidin Domain Receptor 1 metabolism
Interleukin-6 metabolism
Stromal Cells metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1083-351X
- Volume :
- 293
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 29298894
- Full Text :
- https://doi.org/10.1074/jbc.RA117.000672