Osteopontin mediates an MZF1-TGF-beta1-dependent transformation of mesenchymal stem cells into cancer-associated fibroblasts in breast cancer Journal Article

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Authors: Weber, C. E.; Kothari, A. N.; Wai, P. Y.; Li, N. Y.; Driver, J.; Zapf, M. A.; Franzen, C. A.; Gupta, G. N.; Osipo, C; Zlobin, A; Syn, W. K.; Zhang, J; Kuo, P. C.; Mi, Z.
Article Title: Osteopontin mediates an MZF1-TGF-beta1-dependent transformation of mesenchymal stem cells into cancer-associated fibroblasts in breast cancer
Abstract: Interactions between tumor cells and cancer-associated fibroblasts (CAFs) in the tumor microenvironment significantly influence cancer growth and metastasis. Transforming growth factor-beta (TGF-beta) is known to be a critical mediator of the CAF phenotype, and osteopontin (OPN) expression in tumors is associated with more aggressive phenotypes and poor patient outcomes. The potential link between these two pathways has not been previously addressed. Utilizing in vitro studies using human mesenchymal stem cells (MSCs) and MDA-MB231 (OPN+) and MCF7 (OPN-) human breast cancer cell lines, we demonstrate that OPN induces integrin-dependent MSC expression of TGF-beta1 to mediate adoption of the CAF phenotype. This OPN-TGF-beta1 pathway requires the transcription factor, myeloid zinc finger 1 (MZF1). In vivo studies with xenotransplant models in NOD-scid mice showed that OPN expression increases cancer growth and metastasis by mediating MSC-to-CAF transformation in a process that is MZF1 and TGF-beta1 dependent. We conclude that tumor-derived OPN engenders MSC-to-CAF transformation in the microenvironment to promote tumor growth and metastasis via the OPN-MZF1-TGF-beta1 pathway.Oncogene advance online publication, 22 December 2014; doi:10.1038/onc.2014.410.
Journal Title: Oncogene
ISSN: 1476-5594; 0950-9232
Publisher: Unknown  
Date Published: 2014
Start Page: 4821
End Page: 4833
Language: ENG
DOI/URL:

10.1038/onc.2014.410
Notes: LR: 20141225; GR: R21 CA155306/CA/NCI NIH HHS/United States; JID: 8711562; 2014/03/24 [received]; 2014/10/20 [revised]; 2014/11/08 [accepted]; aheadofprint