TGF-β Modulates ovarian cancer invasion by upregulating CAF-Derived versican in the tumor microenvironment

Tsz Lun Yeung; Cecilia S. Leung; Kwong Kwok Wong; Goli Samimi; Melissa S. Thompson; Jinsong Liu; Tarrik M. Zaid; Sue Ghosh; Michael J. Birrer; Samuel C. Mok

doi:10.1158/0008-5472.CAN-13-0023

TGF-β Modulates ovarian cancer invasion by upregulating CAF-Derived versican in the tumor microenvironment

Tsz Lun Yeung, Cecilia S. Leung, Kwong Kwok Wong, Goli Samimi, Melissa S. Thompson, Jinsong Liu, Tarrik M. Zaid, Sue Ghosh, Michael J. Birrer, Samuel C. Mok

Research output: Contribution to journal › Article › peer-review

296 Scopus citations

Abstract

TGF-β has limited effects on ovarian cancer cells, but its contributions to ovarian tumor growth might be mediated through elements of the tumor microenvironment. In the present study, we tested the hypothesis that TGF modulates ovarian cancer progression by modulating the contribution of cancer-associated fibroblasts (CAF) that are present in the microenvironment. Transcriptome profiling of microdissected stromal and epithelial components of high-grade serous ovarian tumors and TGF-β-treated normal ovarian fibroblasts identified versican (VCAN) as a key upregulated target gene in CAFs. Functional evaluations in coculture experiments showed that TGF-β enhanced the aggressiveness of ovarian cancer cells by upregulating VCAN in CAFs. VCAN expression was regulated in CAFs through TGF-β receptor type II and SMAD signaling. Upregulated VCAN promoted the motility and invasion of ovarian cancer cells by activating the NF-kB signaling pathway and by upregulating expression of CD44, matrix metalloproteinase-9, and the hyaluronan-mediated motility receptor. Our work identified a TGF-β-inducible gene signature specific to CAFs in advanced high-grade serous ovarian tumors, and showed how TGF-β stimulates ovarian cancer cell motility and invasion by upregulating the CAF-specific gene VCAN. These findings suggest insights to develop or refine strategies for TGF-β-targeted therapy of ovarian cancer.

Original language	English (US)
Pages (from-to)	5016-5028
Number of pages	13
Journal	Cancer Research
Volume	73
Issue number	16
DOIs	https://doi.org/10.1158/0008-5472.CAN-13-0023
State	Published - Aug 15 2013

ASJC Scopus subject areas

Oncology
Cancer Research

MD Anderson CCSG core facilities

Clinical Trials Office

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10.1158/0008-5472.CAN-13-0023

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title = "TGF-β Modulates ovarian cancer invasion by upregulating CAF-Derived versican in the tumor microenvironment",

abstract = "TGF-β has limited effects on ovarian cancer cells, but its contributions to ovarian tumor growth might be mediated through elements of the tumor microenvironment. In the present study, we tested the hypothesis that TGF modulates ovarian cancer progression by modulating the contribution of cancer-associated fibroblasts (CAF) that are present in the microenvironment. Transcriptome profiling of microdissected stromal and epithelial components of high-grade serous ovarian tumors and TGF-β-treated normal ovarian fibroblasts identified versican (VCAN) as a key upregulated target gene in CAFs. Functional evaluations in coculture experiments showed that TGF-β enhanced the aggressiveness of ovarian cancer cells by upregulating VCAN in CAFs. VCAN expression was regulated in CAFs through TGF-β receptor type II and SMAD signaling. Upregulated VCAN promoted the motility and invasion of ovarian cancer cells by activating the NF-kB signaling pathway and by upregulating expression of CD44, matrix metalloproteinase-9, and the hyaluronan-mediated motility receptor. Our work identified a TGF-β-inducible gene signature specific to CAFs in advanced high-grade serous ovarian tumors, and showed how TGF-β stimulates ovarian cancer cell motility and invasion by upregulating the CAF-specific gene VCAN. These findings suggest insights to develop or refine strategies for TGF-β-targeted therapy of ovarian cancer.",

author = "Yeung, {Tsz Lun} and Leung, {Cecilia S.} and Wong, {Kwong Kwok} and Goli Samimi and Thompson, {Melissa S.} and Jinsong Liu and Zaid, {Tarrik M.} and Sue Ghosh and Birrer, {Michael J.} and Mok, {Samuel C.}",

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T1 - TGF-β Modulates ovarian cancer invasion by upregulating CAF-Derived versican in the tumor microenvironment

AU - Yeung, Tsz Lun

AU - Leung, Cecilia S.

AU - Wong, Kwong Kwok

AU - Samimi, Goli

AU - Thompson, Melissa S.

AU - Liu, Jinsong

AU - Zaid, Tarrik M.

AU - Ghosh, Sue

AU - Birrer, Michael J.

AU - Mok, Samuel C.

PY - 2013/8/15

Y1 - 2013/8/15

N2 - TGF-β has limited effects on ovarian cancer cells, but its contributions to ovarian tumor growth might be mediated through elements of the tumor microenvironment. In the present study, we tested the hypothesis that TGF modulates ovarian cancer progression by modulating the contribution of cancer-associated fibroblasts (CAF) that are present in the microenvironment. Transcriptome profiling of microdissected stromal and epithelial components of high-grade serous ovarian tumors and TGF-β-treated normal ovarian fibroblasts identified versican (VCAN) as a key upregulated target gene in CAFs. Functional evaluations in coculture experiments showed that TGF-β enhanced the aggressiveness of ovarian cancer cells by upregulating VCAN in CAFs. VCAN expression was regulated in CAFs through TGF-β receptor type II and SMAD signaling. Upregulated VCAN promoted the motility and invasion of ovarian cancer cells by activating the NF-kB signaling pathway and by upregulating expression of CD44, matrix metalloproteinase-9, and the hyaluronan-mediated motility receptor. Our work identified a TGF-β-inducible gene signature specific to CAFs in advanced high-grade serous ovarian tumors, and showed how TGF-β stimulates ovarian cancer cell motility and invasion by upregulating the CAF-specific gene VCAN. These findings suggest insights to develop or refine strategies for TGF-β-targeted therapy of ovarian cancer.

AB - TGF-β has limited effects on ovarian cancer cells, but its contributions to ovarian tumor growth might be mediated through elements of the tumor microenvironment. In the present study, we tested the hypothesis that TGF modulates ovarian cancer progression by modulating the contribution of cancer-associated fibroblasts (CAF) that are present in the microenvironment. Transcriptome profiling of microdissected stromal and epithelial components of high-grade serous ovarian tumors and TGF-β-treated normal ovarian fibroblasts identified versican (VCAN) as a key upregulated target gene in CAFs. Functional evaluations in coculture experiments showed that TGF-β enhanced the aggressiveness of ovarian cancer cells by upregulating VCAN in CAFs. VCAN expression was regulated in CAFs through TGF-β receptor type II and SMAD signaling. Upregulated VCAN promoted the motility and invasion of ovarian cancer cells by activating the NF-kB signaling pathway and by upregulating expression of CD44, matrix metalloproteinase-9, and the hyaluronan-mediated motility receptor. Our work identified a TGF-β-inducible gene signature specific to CAFs in advanced high-grade serous ovarian tumors, and showed how TGF-β stimulates ovarian cancer cell motility and invasion by upregulating the CAF-specific gene VCAN. These findings suggest insights to develop or refine strategies for TGF-β-targeted therapy of ovarian cancer.

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TGF-β Modulates ovarian cancer invasion by upregulating CAF-Derived versican in the tumor microenvironment

Abstract

ASJC Scopus subject areas

MD Anderson CCSG core facilities

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