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Osteopontin mediates an MZF1–TGF-β1-dependent transformation of mesenchymal stem cells into cancer-associated fibroblasts in breast cancer

Oncogene volume 34, pages 4821–4833 (2015)Cite this article

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Abstract

Interactions between tumor cells and cancer-associated fibroblasts (CAFs) in the tumor microenvironment significantly influence cancer growth and metastasis. Transforming growth factor-β (TGF-β) 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-β1 to mediate adoption of the CAF phenotype. This OPN–TGF-β1 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-β1 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-β1 pathway.

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Acknowledgements

This research was supported by NIH grants: GM65113, CA155306 and UL1 RR024128. We thank Andy Hall, Research Histology Manager, at the University of Illinois at Chicago Research Resources Center who performed all immunohistochemical staining and mounting. We also thank Dr Dariusz Borys, of the Loyola Department of Pathology, for assistance with the imaging of slides.

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Authors and Affiliations

  1. Department of Surgery, Loyola University Medical Center, Loyola University Chicago, Maywood, IL, USA

    C E Weber, A N Kothari, P Y Wai, N Y Li, J Driver, M A C Zapf, G N Gupta, W K Syn, P C Kuo & Z Mi

  2. The Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Chicago, Maywood, IL, USA

    C E Weber, A N Kothari, P Y Wai, N Y Li, J Driver, M A C Zapf, C A Franzen, G N Gupta, C Osipo, A Zlobin, J Zhang, P C Kuo & Z Mi

  3. Department of Urology, Loyola University Medical Center, Cardinal Bernardin Cancer Center, Loyola University Chicago, Maywood, IL, USA

    C A Franzen & G N Gupta

  4. Liver Unit, Barts Health NHS Trust, London, UK

    W K Syn

  5. Regeneration and Repair, The Institute of Hepatology, London, UK

    W K Syn

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  1. C E Weber
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Weber, C., Kothari, A., Wai, P. et al. Osteopontin mediates an MZF1–TGF-β1-dependent transformation of mesenchymal stem cells into cancer-associated fibroblasts in breast cancer. Oncogene 34, 4821–4833 (2015). https://doi.org/10.1038/onc.2014.410

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