Regulation of Invasion of Epithelial Ovarian Cancer by Transforming Growth Factor-β

Rodriguez, Gustavo C.; Haisley, Camille; Hurteau, Jean; Moser, Tammy L.; Whitaker, Regina S.; Bast, Robert C.; Stack, M. Sharon

doi:10.1006/gyno.2000.6042

Cited by 99 publications

(80 citation statements)

References 33 publications

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“…Our previous work suggested that T␤RIII's tumor-suppressor effects could be partially mediated by the soluble form of T␤RIII (sT␤RIII), possibly by sequestering TGF-␤ (17,20,21). Here we demonstrate that T␤RIII inhibits the migration of cancer cell lines that migrate either in a TGF-␤-responsive (i.e., MDA-MB231 cells) (29) or in a TGF-␤-nonresponsive manner (i.e., Ovca429 cells) (24) (Fig. 1), suggesting that the effects of T␤RIII on cell migration might be independent of its effects on TGF-␤ signaling.…”

Section: T␤riii Suppresses Migration Andmentioning

confidence: 66%

“…shRNA-T␤RIII and the NTC shRNA were both coexpressed with dsRed, allowing for specific inspection of cells expressing the appropriate shRNA. Because NOSE007 cells are epithelial cells lines (24), the majority of single NTC shRNA-infected cells were cuboidal with peripheral actin bundling, reminiscent of an epithelial-like morphology, and lacked significant stress fibers or lamellipodia formation (Fig. 2M).…”

Section: T␤riii Regulates the Actin Cytoskeleton Of Cancer And Epithementioning

confidence: 99%

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The type III TGF-β receptor regulates epithelial and cancer cell migration through β-arrestin2-mediated activation of Cdc42

Mythreye¹,

Blobe

2009

Proc. Natl. Acad. Sci. U.S.A.

127

139

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Loss of expression of the TGF-␤ superfamily coreceptor, the type III TGF-␤ receptor (T␤RIII or betaglycan), occurs in a broad spectrum of human cancers including breast, lung, ovarian, pancreatic, prostate, and renal cell cancer. T␤RIII suppresses cancer progression in vivo, at least in part, by reducing cancer cell motility. However, the mechanism by which T␤RIII regulates migration is unknown. Here, we demonstrate an unexpected TGF-␤ signaling independent role for T␤RIII in activating Cdc42, altering the actin cytoskeleton and reducing directional persistence to inhibit random migration of both cancer and normal epithelial cells. Functionally, T␤RIII through its interaction with the scaffolding protein ␤-arrestin2, activates Cdc42 and inhibits migration. These studies identify a TGF-␤ independent homeostatic function for T␤RIII in regulating cell migration.C ell migration is a complex process required for physiological functions including embryonic development and wound healing. Alterations in cell migration are also critical to disease pathogenesis, including inflammatory and vascular diseases, tumor cell invasion, and metastases (1, 2). The ability of cells to migrate is regulated both by the speed and the directionality of migration that can be triggered by external cues (i.e., chemotaxis) or because of the intrinsic property of cells to migrate (i.e., intrinsic persistence) that are in turn regulated by the Rho family of GTPases, integrins, the actin cytoskelton, and microtubules (3, 4). Several migratory processes in development and tissue remodeling occur without any evidence of extrinsic chemotactic signaling, relying instead on intrinsic cell migratory properties (5).The type III TGF-␤ receptor (T␤RIII/betaglycan), an 849 aa heparan sulfate proteoglycan, is the most abundant and ubiquitously expressed TGF-␤ superfamily coreceptor. T␤RIII has the potential to increase or decrease TGF-␤ signaling through mechanisms yet to be fully defined (6-8). T␤RIII is classically thought to function as a coreceptor, presenting TGF-␤ superfamily ligands to their respective signaling receptors (8). Recent studies have suggested essential, nonredundant roles for T␤RIII in regulating signaling through T␤RII and T␤RI as well as independently of T␤RII and T␤RI (9). T␤RIII null embryos die on embryonic day 13.5, exhibiting hepatic and cardiovascular defects (10). An essential role for T␤RIII has also been demonstrated in mesenchymal transformation during chick embryonic heart development (11, 12) and in mediating TGF-␤ resistance in intestinal goblet cells (13). We have defined essential roles for the cytoplasmic domain of T␤RIII in mediating TGF-␤ signaling independent of the ligand presentation role (14), along with regulating cell-surface levels of T␤RIII and T␤RII through interactions with G␣-interacting protein-interacting protein, C terminus (GIPC) (15) and ␤-arrestin2 (16).Loss of T␤RIII expression has been reported in multiple cancers, with loss of expression correlating with disease progression, advanced stage, or ...

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Section: T␤riii Suppresses Migration Andmentioning

confidence: 66%

Section: T␤riii Regulates the Actin Cytoskeleton Of Cancer And Epithementioning

confidence: 99%

The type III TGF-β receptor regulates epithelial and cancer cell migration through β-arrestin2-mediated activation of Cdc42

Mythreye¹,

Blobe

2009

Proc. Natl. Acad. Sci. U.S.A.

127

139

View full text Add to dashboard Cite

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“…Loss of growth inhibitory effects of TGF-b in OC cells has been attributed in a minority of cases to TGF-b receptor I and II inactivating mutations (Lynch et al, 1998;Chen et al, 2001) or to alterations of cell signaling downstream of SMADs Hu et al, 2000;Baldwin et al, 2003). Like in other malignancies, TGF-b has been linked to increased invasiveness by regulating the expression of proteins involved in metastasis (Rodriguez et al, 2001;Wakahara et al, 2004). Its effects on TG2 illustrated here are likely to contribute to invasion of stroma and OC metastasis, as the enzyme has been strongly implicated in both events (Satpathy et al, 2007).…”

Section: Discussionmentioning

confidence: 77%

Tissue transglutaminase links TGF-β, epithelial to mesenchymal transition and a stem cell phenotype in ovarian cancer

et al. 2011

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Tissue transglutaminase (TG2), an enzyme involved in cell proliferation, differentiation and apoptosis is overexpressed in ovarian carcinomas, where it modulates epithelial-to-mesenchymal transition (EMT) and promotes metastasis. Its regulation in ovarian cancer (OC) remains unexplored. Here, we show that transforming growth factor (TGF)-b, a cytokine involved in tumor dissemination is abundantly secreted in the OC microenvironment and induces TG2 expression and enzymatic activity. This is mediated at transcriptional level by SMADs and by TGFb-activated kinase 1-mediated activation of the nuclear factor-jB complex. TGF-b-stimulated OC cells aggregate as spheroids, which enable peritoneal dissemination. We show that TGF-b-induced TG2 regulates EMT, formation of spheroids and OC metastasis. TG2 knock-down in OC cells decreases the number of cells harboring a cancer stem cell phenotype (CD44 þ /CD117 þ ). Furthermore, CD44 þ /CD117 þ cells isolated from human ovarian tumors express high levels of TG2. In summary, TGFb-induced TG2 enhances ovarian tumor metastasis by inducing EMT and a cancer stem cell phenotype.

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“…19 Briefly, MMP-rich U87 and U118 and MMP-poor TE671 cells at 75% confluency were exposed to 20 mM synthetic fluorogenic MMP substrate DNP-Pro-Leu-Gly-Leu-Trp-Ala-D-Arg-NH 2 (Calbiochem, San Diego, CA, USA) using serum-free conditions at 371C for 5.5 h in triplicate. Media were collected from each sample and separated by reverse-phase HPLC using a C18 column.…”

Section: Assessment Of Mmp Linker Cleavagementioning

confidence: 99%

Targeting the cytotoxicity of fusogenic membrane glycoproteins in gliomas through protease–substrate interaction

Allen

et al. 2003

Gene Ther

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Fusogenic membrane glycoproteins (FMG) are potent therapeutic transgenes with potential utility in the gene therapy of gliomas. FMG expression constructs caused massive syncytia formation followed by cytotoxic cell death in glioma cell lines, and antitumor activity has been shown in glioma xenografts. FMG-induced fusion in glioma cells can involve heterologous cell lines including normal astrocytes and fibroblasts, therefore making targeting important. Here we report on the use of matrix metalloproteinase (MMP) cleavable linkers to target cytotoxicity of FMGs against gliomas. Expression constructs were made expressing the hyperfusogenic version of the Gibbon Ape Leukemia Virus envelope glycoprotein (GALV) linked to a blocking ligand (the C-terminal extracellular domain of CD40 ligand) via either an MMP cleavable linker (GALV M40), a factor Xa protease cleavable linker (GALV X40), or a noncleavable linker (GALV N40). Unmodified GALV expressing constructs were used as positive controls. The glioma cell lines U87, U118, and U251 previously characterized by zymography and MMP-2 activity assay as high, medium, and low MMP expressors, respectively; normal human astrocytes and the MMP-poor cell line TE671 were transfected with the GALV, GALV N40, GALV X40, and GALV M40 constructs. In contrast to unmodified GALV constructs, transfection with GALV X40 and GALV N40 constructs blocked fusion and cytotoxic cell death. Fusion occurred, however, after transfection with constructs containing MMP cleavable linkers to an extent dependent on MMP expression in the specific cell line. Use of the broad-spectrum MMP inhibitors, 1,10-phenanthroline and N-hydroxy-piperazine-carboxamide completely abolished the ability of MMP constructs to induce fusion. In cell mixing experiments, mixing of MMP-poor cell lines transfected with GALV M40 constructs with the MMP overexpressing untransfected U87 glioma cells led to partial restoration of fusion. Use of U87 supernatant did result in a similar effect. Establishment of stable tranfectants expressing the membrane-type MMPs, MT-1 MMP and MT-2 MMP did restore fusion in the MMP-poor cell line TE671 after transfection with GALV M40, thus indicating that both membrane-type MMPs and soluble MMPs activate the MMP cleavable constructs. In addition, the GALV M40 construct retained its cytotoxic activity against U87 cells in vivo, although less effectively as compared to unmodified GALV. Our data indicate that GALV-induced cytotoxicity in glioma cell lines can be blocked by display of the CD40 ligand. Incorporation of an MMP cleavable linker can selectively restore cytotoxicity in MMP expressing glioma cell lines both in vitro and in vivo, while sparing normal human astrocytes. Given the high frequency of MMP overexpression in gliomas, this represents a promising targeting strategy. Gene Therapy (2003) 10, 725-732.

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Regulation of Invasion of Epithelial Ovarian Cancer by Transforming Growth Factor-β

Cited by 99 publications

References 33 publications

The type III TGF-β receptor regulates epithelial and cancer cell migration through β-arrestin2-mediated activation of Cdc42

The type III TGF-β receptor regulates epithelial and cancer cell migration through β-arrestin2-mediated activation of Cdc42

Tissue transglutaminase links TGF-β, epithelial to mesenchymal transition and a stem cell phenotype in ovarian cancer

Targeting the cytotoxicity of fusogenic membrane glycoproteins in gliomas through protease–substrate interaction

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