title: Osteopontin mediates an MZF1-TGF-β1-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-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.
authors.affiliation: 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.
authors.forename: C E
authors.initials: CE
authors.lastname: Weber
authors.affiliation: 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.
authors.forename: A N
authors.initials: AN
authors.lastname: Kothari
authors.affiliation: 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.
authors.forename: P Y
authors.initials: PY
authors.lastname: Wai
authors.affiliation: 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.
authors.forename: N Y
authors.initials: NY
authors.lastname: Li
authors.affiliation: 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.
authors.forename: J
authors.initials: J
authors.lastname: Driver
authors.affiliation: 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.
authors.forename: M A C
authors.initials: MA
authors.lastname: Zapf
authors.affiliation: 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.
authors.forename: C A
authors.initials: CA
authors.lastname: Franzen
authors.affiliation: 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.
authors.forename: G N
authors.initials: GN
authors.lastname: Gupta
authors.affiliation: The Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Chicago, Maywood, IL, USA.
authors.forename: C
authors.initials: C
authors.lastname: Osipo
authors.affiliation: The Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Chicago, Maywood, IL, USA.
authors.forename: A
authors.initials: A
authors.lastname: Zlobin
authors.affiliation: Department of Surgery, Loyola University Medical Center, Loyola University Chicago, Maywood, IL, USA.|Liver Unit, Barts Health NHS Trust, London, UK.|Regeneration and Repair, The Institute of Hepatology, London, UK.
authors.forename: W K
authors.initials: WK
authors.lastname: Syn
authors.affiliation: The Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Chicago, Maywood, IL, USA.
authors.forename: J
authors.initials: J
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: P C
authors.initials: PC
authors.lastname: Kuo
authors.affiliation: 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.
authors.forename: Z
authors.initials: Z
authors.lastname: Mi
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D061986:MCF-7 Cells; D059630:Mesenchymal Stem Cells / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D053495:Osteopontin / Q000494:pharmacology / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D051741:Kruppel-Like Transcription Factors; C085969:MZF1 protein, human; D053773:Transforming Growth Factor beta1; D053495:Osteopontin