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Transforming growth factor-β (TGF-β) is known to be a critical mediator of the cancer associated fibroblast (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 well characterized. In human breast cancer and hepatocellular cancer models (HCC), OPN induces mesenchymal stem cell (MSC)-to-CAF transformation. OPN binds to cell-surface integrin receptors to activate the transcription factor, myeloid zinc finger 1 (MZF1) to induce MSC production of TGF-β1. OPN induces MZF1 protein to positively feedback regulate its own transcription via binding to the MZF1 promoter and further enhance TGF-β1 expression. The adoption of the CAF phenotype is associated with increased local tumor growth and metastases. Blockade of OPN abolishes this MZF1-TGF-β1 mediated MSC-to-CAF transformation. This suggests interrupting the MZF1-dependent elaboration of TGF-β by blockade of OPN may be an effective clinical strategy for tumor growth inhibition. This review will describe the regulatory pathways by which OPN and MZF1 mediated TGF-β expression induces the CAF phenotype to potentiate cancer growth and metastasis. *Correspondence to: Paul C Kuo, MD, USF Department of Surgery, 2 Tampa General Circle, Rm 7015, Tampa, FL 33606, USA, Tel: 813-250-2572; E-mail: paulkuo@health.usf.edu Received: April 20, 2018; Accepted: May 02, 2018; Published: May 07, 2018 Introduction Interactions between tumor cells and cancer-associated fibroblasts (CAFs) in the tumor microenvironment (TMEN) significantly influence cancer growth and metastasis. Tumor growth and metastasis is highly dependent on complex dynamic interactions between cancer cells and tumor stroma, mediated by direct cell-cell contact and secreted growth factors and cytokines. CAFs, a tumor stromal element, are involved in tumor growth potentiation, extracellular matrix degradation, tumor cell motility, inhibition of host anti-tumor response, promotion of angiogenesis and metastasis. CAF origin is likely multifactorial, derived from local fibroblasts, bone marrow-mesenchymal stem cells (MSCs), pericytes and tumor cells. Specific molecular markers and signaling pathways that mediate CAF activation are poorly understood. Nevertheless, it is generally accepted that α-smooth muscle actin (SMA), tenascin-C, vimentin and fibroblast specific protein-1 (FSP-1), among others, describe the CAF phenotype [1,2]. Transforming growth factor-β (TGF-β) is known to be a critical mediator of the CAF phenotype. TGF-β is critical for CAF activation and elaboration of a protumorigenic microenvironment [3-6]. Signaling by TGF-β regulates tumor initiation, progression and metastasis through tumor cellautonomous and host–tumor interactions. TGF-β mediates fibroblast differentiation, tumor stroma formation and regulates all stages of tumor development via tumor cell-autonomous and host-tumor interactions [3-6]. Resident fibroblasts and bone marrow-derived MSCs convert into CAFs during tumor progression. A TGF-β autocrine/ paracrine signaling loop acts to initiate/maintain this CAF phenotype and CAFs increase tumor invasion [7-10]. The loss of TGF-β1 reverses this growth advantage imparted by CAFs [11]. The process wherein epithelial cells differentiate back into ECMsecreting mesenchymal stem cells is termed epithelial mesenchymal transition (EMT). Epithelial cells lose their cell-cell adhesions, polarity, and epithelial cell markers and gain mobility and mesenchymal cell markers. As such, EMT is vital to the physiologic process of wound healing and the pathologic process of metastasis. Various transcription factors and signaling pathways act to induce EMT and promote either the epithelial or mesenchymal phenotype, including TGF-β, an important suppressor of epithelial cell proliferation and inducer of tumor progression and metastasis. TGF-β is secreted from the tumor stroma in many malignancies, largely sourced from CAFs [7]. CAFderived TGF-β can induce EMT in several tumors via a multitude of mechanisms. Breast cancer cell lines undergo EMT in response to treatment with conditioned medium from CAFs isolated from invasive breast specimens. In this model, neutralizing antibody and smallmolecule inhibition of TGF-β signaling prevents EMT in these cell lines [12]. TGF-β secreted by CAFs can also lead to EMT in bladder cancer cells, a process regulated by the long-coding RNA ZEB2NAT. Following the depletion of lncRNA-ZEB2NAT, conditioned media from CAFs fail to induce EMT in human bladder cancer cell lines (5637, T24, and J82) [13]. TGF-β can also result in the formation of cancer stem cell populations within tumors—a process attributable to EMT. For example, TGF-β treatment of patient-derived colorectal tumor specimens results Kuo MC (2018) Osteopontin-myeloid zinc finger 1 signaling regulates transforming growth factor-β expression in cancer Volume 2(3): 2-16 Cancer Rep Rev, 2018 doi: 10.15761/CRR.1000152 in upregulation of CD44+ stem cell populations and expression of N-cadherin. This suggests that TGF-β induces the formation of cancer stem cells through EMT [14]. In non-small cell lung cancer, TGF-β has a similar effect on cancer stemness [15]. Another intermediate for TGF-β-related acquisition of cancer stemness is miR-155 which, when overexpressed, results in EMT in liver cancer [16]. These studies demonstrated the role of TGF-β signaling in CAF initiation and maintenance, leading to EMT. However, the initiating steps for TGF-β synthesis in this context have never been addressed. Osteopontin (OPN), a phosphoprotein secreted by malignant cells and tumor stromal cells, is a key mediator of tumor cell migration and metastasis and a marker of breast cancer progression and metastasis [17-23]. Recent findings suggest that tumor-derived OPN instigates bone marrow-derived MSC trafficking to the TMEN [24-26], which is characterized by the outgrowth of a desmoplastic stroma rich in CAFs that promotes cancer growth and metastasis [24,25,27]. Serendipitously, OPN induces TGF-β expression and fibroblast activation in models of inflammation and fibrosis [28,35]. In our previous work with in vitro and in vivo human cancer models, we found that OPN induces MSC-to-CAF transformation. OPN binds to cell-surface integrin receptors to activate the transcription factor, myeloid zinc finger 1 (MZF1), and induce MSC production of TGF-β1 with increased CAF phenotype markers. The adoption of the CAF phenotype is associated with increased local tumor growth and metastases. Extracellular blockade of OPN abolishes this MZF1-TGF-β1 mediated MSC-to-CAF transformation. However, the relationship between OPN, TGF-β and the CAF phenotype remains poorly understood. This review will describe the regulatory pathways by which OPN and MZF1 mediated TGF-β expression induces the CAF phenotype to potentiate cancer growth and metastasis.

Osteopontin-myeloid zinc finger 1 signaling regulates transforming growth factor-ß expression in cancer