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Sphingosine kinase 1 is required for TGF-? mediated fibroblastto- myofibroblast differentiation in ovarian cancer.

ABSTRACT: Sphingosine kinase 1 (SPHK1), the enzyme that produces sphingosine 1 phosphate (S1P), is known to be highly expressed in many cancers. However, the role of SPHK1 in cells of the tumor stroma remains unclear. Here, we show that SPHK1 is highly expressed in the tumor stroma of high-grade serous ovarian cancer (HGSC), and is required for the differentiation and tumor promoting function of cancer-associated fibroblasts (CAFs). Knockout or pharmacological inhibition of SPHK1 in ovarian fibroblasts attenuated TGF-?-induced expression of CAF markers, and reduced their ability to promote ovarian cancer cell migration and invasion in a coculture system. Mechanistically, we determined that SPHK1 mediates TGF-? signaling via the transactivation of S1P receptors (S1PR2 and S1PR3), leading to p38 MAPK phosphorylation. The importance of stromal SPHK1 in tumorigenesis was confirmed in vivo, by demonstrating a significant reduction of tumor growth and metastasis in SPHK1 knockout mice. Collectively, these findings demonstrate the potential of SPHK1 inhibition as a novel stroma-targeted therapy in HGSC.

SUBMITTER: Beach JA

PROVIDER: S-EPMC4826197 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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Sphingosine kinase 1 is required for TGF-β mediated fibroblastto- myofibroblast differentiation in ovarian cancer.

Beach Jessica A JA Aspuria Paul-Joseph P PJ Cheon Dong-Joo DJ Lawrenson Kate K Agadjanian Hasmik H Walsh Christine S CS Karlan Beth Y BY Orsulic Sandra S

Oncotarget 20160101 4

Sphingosine kinase 1 (SPHK1), the enzyme that produces sphingosine 1 phosphate (S1P), is known to be highly expressed in many cancers. However, the role of SPHK1 in cells of the tumor stroma remains unclear. Here, we show that SPHK1 is highly expressed in the tumor stroma of high-grade serous ovarian cancer (HGSC), and is required for the differentiation and tumor promoting function of cancer-associated fibroblasts (CAFs). Knockout or pharmacological inhibition of SPHK1 in ovarian fibroblasts at ...[more]

PMID: 26716409

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Project description:Tumor microenvironment contains various components including cancer cells, tumor vessels, and cancer associated fibroblasts (CAFs), comprising of tumor-promoting myofibroblasts and tumor-suppressing fibroblasts. Multiple lines of evidence indicated that transforming growth factor-β (TGF-β) induces the formation of myofibroblasts and other types of mesenchymal (non-myofibroblastic) cells from endothelial cells. Recent reports showed that fibroblast growth factor 2 (FGF2) modulates TGF-β-induced mesenchymal transition of endothelial cells, but the molecular mechanisms regarding the signals that control the transcriptional networks during the formation of different groups of fibroblasts remain largely unclear. Here, we studied the roles of FGF2 during the regulation of TGF-β-induced mesenchymal transition of tumor endothelial cells (TECs). We demonstrated that auto/paracrine FGF signals in TECs inhibit TGF-β-induced endothelial-to-myofibroblast transition (End-MyoT), leading to suppressed formation of contractile myofibroblast cells, but on the other hand can also collaborate with TGF-β in promoting the formation of active fibroblastic cells which have migratory and proliferative properties. FGF2 modulated TGF-β-induced formation of myofibroblastic and non-myofibroblastic cells from TECs via transcriptional regulation of the array of various mesenchymal markers and growth factors. Furthermore, we observed that TECs treated with TGF-β were more competent in promoting in vivo tumor growth than TECs treated with TGF-β and FGF2. Mechanistically, we showed that Elk1 mediated this FGF2-induced inhibition of End-MyoT via inhibition of TGF-β-induced transcriptional activation of α-SMA promoter by myocardin-related transcription factor (MRTF)-A. Our data suggest that TGF-β and FGF2 oppose and cooperate with each other during the formation of myofibroblastic and non-myofibroblastic cells from TECs to determine the characteristics of the mesenchymal cells in tumor microenvironment. Identification of marker genes for TGF-β-induced endothelial-to-myofibroblast transition

Dataset Information

Sphingosine kinase 1 is required for TGF-? mediated fibroblastto- myofibroblast differentiation in ovarian cancer.

Publications

Sphingosine kinase 1 is required for TGF-β mediated fibroblastto- myofibroblast differentiation in ovarian cancer.

Similar Datasets

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