Signaling pathway cooperation in TGF-β-induced epithelial–mesenchymal transition

Derynck, Rik; Muthusamy, Baby Periyanayaki; Saeteurn, Koy

doi:10.1016/j.ceb.2014.09.001

Cited by 324 publications

(298 citation statements)

References 118 publications

(132 reference statements)

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“…19,31 In addition to the canonical pathway, the TGF-b/mammalian target of rapamycin pathway is also involved in MMT. 19,30 In TGF-beinduced MMT, SNAIL1 was shown to down-regulate CDH1 expression and thereby induce MMT, similar to the mechanism of cancer metastasis. 20,30,33 However, we could not detect CDH1 expression in either peritoneal or liver MCs by immunohistochemistry in mice.…”

Section: On the Basis Of The Labeling Efficiency Of Mcs In The Wt1mentioning

confidence: 96%

“…19,30 In TGF-beinduced MMT, SNAIL1 was shown to down-regulate CDH1 expression and thereby induce MMT, similar to the mechanism of cancer metastasis. 20,30,33 However, we could not detect CDH1 expression in either peritoneal or liver MCs by immunohistochemistry in mice. 12 Cultured MCs express Snai1 at a low level (data not shown).…”

Section: On the Basis Of The Labeling Efficiency Of Mcs In The Wt1mentioning

confidence: 96%

“…TGF-b is known to induce fibrosis in organs by activating myofibroblasts, whereas it suppresses inflammation and carcinogenesis in epithelial cells. 30 In fact, the overexpression of a STR plasmid enhanced inflammation and failed to attenuate 32 Canonical TGF-b signaling is mediated by SMAD2/3. 30 In MCs, SMAD3, but not SMAD2, mediates MMT.…”

Section: On the Basis Of The Labeling Efficiency Of Mcs In The Wt1mentioning

confidence: 99%

“…30 In fact, the overexpression of a STR plasmid enhanced inflammation and failed to attenuate 32 Canonical TGF-b signaling is mediated by SMAD2/3. 30 In MCs, SMAD3, but not SMAD2, mediates MMT. 19,31 In addition to the canonical pathway, the TGF-b/mammalian target of rapamycin pathway is also involved in MMT.…”

Section: On the Basis Of The Labeling Efficiency Of Mcs In The Wt1mentioning

confidence: 99%

See 3 more Smart Citations

Myofibroblastic Conversion and Regeneration of Mesothelial Cells in Peritoneal and Liver Fibrosis

Lua

Pappoe

et al. 2015

The American Journal of Pathology

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Section: On the Basis Of The Labeling Efficiency Of Mcs In The Wt1mentioning

confidence: 96%

Section: On the Basis Of The Labeling Efficiency Of Mcs In The Wt1mentioning

confidence: 96%

Section: On the Basis Of The Labeling Efficiency Of Mcs In The Wt1mentioning

confidence: 99%

Section: On the Basis Of The Labeling Efficiency Of Mcs In The Wt1mentioning

confidence: 99%

See 2 more Smart Citations

Myofibroblastic Conversion and Regeneration of Mesothelial Cells in Peritoneal and Liver Fibrosis

Lua

Pappoe

et al. 2015

The American Journal of Pathology

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“…On the other hand, advanced tumors are frequently found with high levels of TGF-b that promotes tumor progression by inducing epithelial to mesenchymal transition (EMT) and invasion. 4,5 Several key transcriptional targets of TGF-b including Snail Family Zinc Finger 1 (SNAl1), Zinc finger E-box binding homeobox 1 (ZEB1), high mobility group AT-Hook 2 (HMGA2), and forkhead box A1 (FOXA1) have been shown to play important roles in TGF-b-induced EMT, while other nontranscriptional mechanisms have also been reported. Despite a vast body of the literature on the nuts and bolts of how TGF-b signals, the mechanism that underpins the switch of TGF-b from a growth inhibitor to a tumor promoter still remains elusive.…”

mentioning

confidence: 99%

Redirecting RNA splicing by SMAD3 turns TGF-β into a tumor promoter

Tripathi

Zhang

2016

Molecular & Cellular Oncology

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Transforming growth factor b (TGF-b) is a well-known growth inhibitor of normal epithelial cells, but it is also secreted by solid tumors to promote cancer progression. Our recent discovery of SMAD3-PCBP1 complex with direct RNA-binding properties has shed light on how this conversion is implemented by controlling pre-mRNA splicing patterns. Transforming growth factor b (TGF-b) is well known to be a potent growth inhibitor and tumor suppressor; however, at the time when TGF-b was discovered, it was first identified as an activity that transformed normal fibroblasts to form colonies in soft-agar in cooperation with epidermal growth factor (EGF) or TGF-a, both of which are ligands of EGF receptors (EGFR). 1 Fast forward 35 y to present time, it has been appreciated that the two seemingly opposing functions of TGF-b are cell-contextual dependent: in normal epithelial, endothelial, and hematopoietic cells. TGF-b strongly inhibits growth, but this inhibition is lost in late stages of carcinomas with elevated levels of signaling from the mitogen-activated protein kinase (MAPK) pathway sustained by oncogenic mutations. 2,3 Multiple mechanisms by which TGF-b inhibits cell growth have been unraveled, chief among them are transcriptional induction of cyclin dependent kinase (CDK) inhibitors and suppression of proto-oncogene MYC and apoptosis inducer B-cell lymphoma 2 (BCL2). On the other hand, advanced tumors are frequently found with high levels of TGF-b that promotes tumor progression by inducing epithelial to mesenchymal transition (EMT) and invasion. 4,5 Several key transcriptional targets of TGF-b including Snail Family Zinc Finger 1 (SNAl1), Zinc finger E-box binding homeobox 1 (ZEB1), high mobility group AT-Hook 2 (HMGA2), and forkhead box A1 (FOXA1) have been shown to play important roles in TGF-b-induced EMT, while other nontranscriptional mechanisms have also been reported. Despite a vast body of the literature on the nuts and bolts of how TGF-b signals, the mechanism that underpins the switch of TGF-b from a growth inhibitor to a tumor promoter still remains elusive. In searching for proteins that confer regulation of the key TGF-b pathway transcription effector SMAD3 via phosphorylation of threonine 179 (T179) in the linker region, we identified an RNA-binding protein poly(RC) binding protein 1 (PCBP1, also known as hnRNP E1), and serendipitously discovered that by partnering with PCBP1, SMAD3 is brought onto the pre-mRNA of a cancer stem cell marker gene CD44 to regulate its alternative splicing. 6 In addition to CD44, our global RNA-seq study revealed a plethora of cancers genes whose splicing patterns are altered by the SMAD3-PCBP1 interaction in favor of tumor progression. These findings let us to propose that regulation of alternative splicing by the concerted action of receptor-activated SMAD3 and PCBP1 is a key mechanism that propels TGF-b to a tumor promoter (Fig. 1).According to the current paradigm of TGF-b signaling, SMAD3 is activated by phosphorylation at the carboxyl terminus SSXS motif b...

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Reducing tumor invasiveness by ramucirumab and TGF‐β receptor kinase inhibitor in a diffuse‐type gastric cancer patient‐derived cell model

Lee

Byeon

et al. 2021

Cancer Medicine

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Background Diffuse‐type gastric cancer (GC) is known to be more aggressive and relatively resistant to conventional chemotherapy. Hence, more optimized treatment strategy is urgently needed in diffuse‐type GC. Methods Using a panel of 10 GC cell lines and 3 GC patient‐derived cells (PDCs), we identified cell lines with high EMTness which is a distinct feature for diffuse‐type GC. We treated GC cells with high EMTness with ramucirumab alone, TGF‐β receptor kinase inhibitor (TEW‐7197) alone, or in combination to investigate the drug's effects on invasiveness, spheroid formation, EMT marker expression, and tumor‐induced angiogenesis using a spheroid‐on‐a‐chip model. Results Both TEW‐7197 and ramucirumab treatments profoundly decreased invasiveness of EMT‐high cell lines and PDCs. With a 3D tumor spheroid‐on‐a‐chip, we identified versatile influence of co‐treatment on cancer cell‐induced blood vessel formation as well as on EMT progression in tumor spheroids. The 3D tumor spheroid‐on‐a‐chip demonstrated that TEW‐7197 + ramucirumab combination significantly decreased PDC‐induced vessel formation. Conclusions In this study, we showed TEW‐7197 and ramucirumab considerably decreased invasiveness, thus EMTness in a panel of diffuse‐type GC cell lines including GC PDCs. Taken together, we confirmed that combination of TEW‐7197 and ramucirumab reduced tumor spheroid and GC PDC‐induced blood vessel formation concomitantly in the spheroid‐on‐a‐chip model.

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Signaling pathway cooperation in TGF-β-induced epithelial–mesenchymal transition

Cited by 324 publications

References 118 publications

Myofibroblastic Conversion and Regeneration of Mesothelial Cells in Peritoneal and Liver Fibrosis

Myofibroblastic Conversion and Regeneration of Mesothelial Cells in Peritoneal and Liver Fibrosis

Redirecting RNA splicing by SMAD3 turns TGF-β into a tumor promoter

Reducing tumor invasiveness by ramucirumab and TGF‐β receptor kinase inhibitor in a diffuse‐type gastric cancer patient‐derived cell model

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