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

Cao, Liyun; Shao, Minghai; Schilder, Jeanne M.; Guise, Theresa A.; Mohammad, Khalid S.; Matei, Daniela

doi:10.1038/onc.2011.429

Cited by 192 publications

(214 citation statements)

References 49 publications

(61 reference statements)

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“…We showed previously that TGFb signaling was present in spheroids . This is consistent with TGFb treatment regulating tissue transglutaminase 2 in ovarian cancer cells to promote EMT and spheroid formation (Cao et al 2012). In the present report, we have now uncovered a new function for active maintenance of endogenous TGFb signaling in promoting the EMT phenotype of spheroids and their potential to reattach and spread.…”

Section: Discussionsupporting

confidence: 71%

TGFβ signaling regulates epithelial–mesenchymal plasticity in ovarian cancer ascites-derived spheroids

Rafehi¹,

Valdes²,

Bertrand³

et al. 2015

Endocrine-Related Cancer

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Epithelial-mesenchymal transition (EMT) serves as a key mechanism driving tumor cell migration, invasion, and metastasis in many carcinomas. Transforming growth factor-beta (TGFb) signaling is implicated in several steps during cancer pathogenesis and acts as a classical inducer of EMT. Since epithelial ovarian cancer (EOC) cells have the potential to switch between epithelial and mesenchymal states during metastasis, we predicted that modulation of TGFb signaling would significantly impact EMT and the malignant potential of EOC spheroid cells. Ovarian cancer patient ascites-derived cells naturally underwent an EMT response when aggregating into spheroids, and this was reversed upon spheroid re-attachment to a substratum. CDH1/E-cadherin expression was markedly reduced in spheroids compared with adherent cells, in concert with an up-regulation of several transcriptional repressors, i.e., SNAI1/Snail, TWIST1/2, and ZEB2. Treatment of EOC spheroids with the TGFb type I receptor inhibitor, SB-431542, potently blocked the endogenous activation of EMT in spheroids. Furthermore, treatment of spheroids with SB-431542 upon re-attachment enhanced the epithelial phenotype of dispersing cells and significantly decreased cell motility and Transwell migration. Spheroid formation was significantly compromised by exposure to SB-431542 that correlated with a reduction in cell viability particularly in combination with carboplatin treatment. Thus, our findings are the first to demonstrate that intact TGFb signaling is required to control EMT in EOC ascites-derived cell spheroids, and it promotes the malignant characteristics of these structures. As such, we show the therapeutic potential for targeted inhibition of this pathway in ovarian cancer patients with late-stage disease.

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Section: Discussionsupporting

confidence: 71%

TGFβ signaling regulates epithelial–mesenchymal plasticity in ovarian cancer ascites-derived spheroids

Rafehi¹,

Valdes²,

Bertrand³

et al. 2015

Endocrine-Related Cancer

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“…Snail overexpression in tumour cells is able to promote VM formation induced by EMT and increased CSCs, exhibit a better capability of growth and invasion [58][59][60]. It can be verified that snail is overexpressed in highly aggressive tumour cells but not in normal tissues.…”

Section: Snailmentioning

confidence: 99%

The relationship between vasculogenic mimicry and epithelial‐mesenchymal transitions

Liu

Qiao

Liang

et al. 2016

J Cellular Molecular Medi

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Vasculogenic mimicry ( VM ) is a vascular‐like structure which can mimic the embryonic vascular network pattern to nourish the tumour tissue. As a unique perfusion way, VM is correlated with tumour progression, invasion, metastasis and lower 5‐year survival rate. Notably, epithelial‐mesenchymal transition ( EMT ) regulators and EMT ‐related transcription factors are highly up‐regulated in VM ‐forming tumour cells, which demonstrated that EMT may play a crucial role in VM formation. Therefore, the up‐regulation of EMT ‐associated adhesion molecules and other factors can also make a contribution in VM ‐forming process. Depending on these discoveries, VM and EMT can be utilized as therapeutic target strategies for anticancer therapy. The purpose of this article is to explore the advance research in the relationship of EMT and VM and their corresponding mechanisms in tumorigenesis effect.

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“…19 Signaling from TGF-b has been shown by us and others to be functional in ovarian cancer, [15][16][17] acting as a potent inducer of ovarian cancer invasiveness by regulating proteins involved in metastasis 18,19 and contributing to EMT and increased metastasis. 20 TGF-b ligands and type I and type II TGF-b receptors are expressed in over 50% of ovarian tumors, [21][22][23] and TGF-b is abundantly secreted in the peritoneal environment by both cancer and stromal cells. 15 Although a known inhibitor of epithelial cell proliferation, 24 TGF-b growth inhibitory signals have been shown to be blocked in malignancy, resulting in neoplastic epithelial cell insensitivity to TGF-b.…”

Section: Introductionmentioning

confidence: 99%

TGF-β induces global changes in DNA methylation during the epithelial-to-mesenchymal transition in ovarian cancer cells

Cárdenas¹,

et al. 2014

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A key step in the process of metastasis is the epithelial-to-mesenchymal transition (EMT). We hypothesized that epigenetic mechanisms play a key role in EMT and to test this hypothesis we analyzed global and gene-specific changes in DNA methylation during TGF-b-induced EMT in ovarian cancer cells. Epigenetic profiling using the Infinium HumanMethylation450 BeadChip (HM450) revealed extensive (P < 0.01) methylation changes after TGF-b stimulation (468 and 390 CpG sites altered at 48 and 120 h post cytokine treatment, respectively). The majority of gene-specific TGF-b-induced methylation changes occurred in CpG islands located in or near promoters (193 and 494 genes hypermethylated at 48 and 120 h after TGF-b stimulation, respectively). Furthermore, methylation changes were sustained for the duration of TGF-b treatment and reversible after the cytokine removal. Pathway analysis of the hypermethylated loci identified functional networks strongly associated with EMT and cancer progression, including cellular movement, cell cycle, organ morphology, cellular development, and cell death and survival. Altered methylation and corresponding expression of specific genes during TGF-b-induced EMT included CDH1 (E-cadherin) and COL1A1 (collagen 1A1). Furthermore, TGF-b induced both expression and activity of DNA methyltransferases (DNMT) -1, -3A, and -3B, and treatment with the DNMT inhibitor SGI-110 prevented TGF-b-induced EMT. These results demonstrate that dynamic changes in the DNA methylome are implicated in TGF-b-induced EMT and metastasis. We suggest that targeting DNMTs may inhibit this process by reversing the EMT genes silenced by DNA methylation in cancer.

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

Cited by 192 publications

References 49 publications

TGFβ signaling regulates epithelial–mesenchymal plasticity in ovarian cancer ascites-derived spheroids

TGFβ signaling regulates epithelial–mesenchymal plasticity in ovarian cancer ascites-derived spheroids

The relationship between vasculogenic mimicry and epithelial‐mesenchymal transitions

TGF-β induces global changes in DNA methylation during the epithelial-to-mesenchymal transition in ovarian cancer cells

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