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Oncogene. 2015 Sep 10;34(37):4821-33. doi: 10.1038/onc.2014.410. Epub 2014 Dec 22.

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

Weber CE1,2, Kothari AN1,2, Wai PY1,2, Li NY1,2, Driver J1,2, Zapf MA1,2, Franzen CA2,3, Gupta GN1,2,3, Osipo C2, Zlobin A2, Syn WK1,4,5, Zhang J2, Kuo PC1,2, Mi Z1,2.

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Department of Surgery, Loyola University Medical Center, Loyola University Chicago, Maywood, IL, USA.
The Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Chicago, Maywood, IL, USA.
Department of Urology, Loyola University Medical Center, Cardinal Bernardin Cancer Center, Loyola University Chicago, Maywood, IL, USA.
Liver Unit, Barts Health NHS Trust, London, UK.
Regeneration and Repair, The Institute of Hepatology, London, UK.


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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