Abstract
The importance of immunosuppressive myeloid-derived suppressor cells (MDSCs) bearing monocyte markers in tumor metastasis has been well established. Recently, it was reported that these cells possess phenotypic plasticity and differentiate into fibrocytes, very distinct cells that are precursors of tumorigenic myofibroblasts. However, the importance of this transdifferentiation in tumor metastasis has not been explored. Here, we describe the role of MDSC-derived fibrocytes in tumor metastasis that is regulated by Kruppel-like factor 4 (KLF4), a transcription factor that is critical to monocyte differentiation and to promotion of cancer development. Using mouse metastasis models of melanoma and breast cancer, we found that KLF4 knockout was associated with significantly reduced pulmonary metastasis, which was accompanied by decreased populations of MDSCs, fibrocytes and myofibroblasts in the lung. Cause-effect studies by adoptive transfer revealed that KLF4 deficiency in MDSCs led to significantly reduced lung metastasis that was associated with fewer MDSC-derived fibrocytes and myofibroblasts. Mechanistically, KLF4 deficiency significantly compromised the generation of fibrocytes from MDSCs in vitro. During this process, KLF4 expression levels were tightly linked with those of fibroblast-specific protein-1 (FSP-1), deficiency of which resulted in no metastasis in mice as has been previously reported. In addition, KLF4 bound directly to the FSP-1 promoter as determined by chromatin immunoprecipitation and overexpression of KLF4 increased the FSP-1 promoter activities. Taken together, our results suggest that MDSCs not only execute their immunosuppressive function to promote metastatic seeding as reported before, but also boost metastatic tumor growth after they adopt a fibrocyte fate. Therefore, KLF4-mediated fibrocyte generation from MDSCs may represent a novel mechanism of MDSCs contributing to tumor metastasis and supports the feasibility of inhibiting KLF4 or FSP-1 to prevent tumor metastasis.
Document Type
Article
Publication Date
11-24-2014
Digital Object Identifier (DOI)
http://dx.doi.org/10.1038/oncsis.2014.44
Funding Information
Grant: this work was supported by Research Development Fund (RDF) from University of South Carolina School of Medicine and ASPIRE-I from University of South Carolina to WA.
Repository Citation
Shi, Y.; Ou, L.; Han, S.; Li, M.; Pena, M. M. O.; Pena, E. A.; Liu, Chunming; Nagarkatti, M.; Fan, D.; and Ai, W., "Deficiency of Kruppel-Like Factor KLF4 in Myeloid-Derived Suppressor Cells Inhibits Tumor Pulmonary Metastasis in Mice Accompanied by Decreased Fibrocytes" (2014). Molecular and Cellular Biochemistry Faculty Publications. 76.
https://uknowledge.uky.edu/biochem_facpub/76
Supplementary Figures (PDF)
oncsis201444x2.doc (98 kB)
Supplementary Figures (DOC)
oncsis201444x3.doc (31 kB)
Supplementary Table
Notes/Citation Information
Published in Oncogenesis, v. 3, article e129, p. 1-7.
© 2014 Macmillan Publishers Limited
Oncogenesis is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.