A novel tumor‐based epithelial‐to‐mesenchymal transition score that associates with prognosis and metastasis in patients with Stage II/III colorectal cancer

Roseweir, Antonia K.; Kong, Chia Yew; Park, J.H.; Bennett, Louise; Powell, Arfon; Quinn, Jean A.; Wyk, Hester C. van; Horgan, Paul G.; McMillan, Donald C.; Edwards, Joanne; Roxburgh, Campbell S.D.

doi:10.1002/ijc.31739

Cited by 30 publications

(46 citation statements)

References 36 publications

(93 reference statements)

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“…Previous studies indicate that stimulating EMT and increasing CSCs can promote cancer metastasis and relapse . Cells undergoing EMT are known to acquire stem cell‐like properties.…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies indicate that stimulating EMT and increasing CSCs can promote cancer metastasis and relapse. 34,[47][48][49][50] Cells undergoing EMT are known to acquire stem cell-like properties. Loss of epithelial marker E-cadherin, increased expression of mesenchymal markers Fibronectin and Vimentin and the EMT regulator Snail, which are important events in EMT.…”

Section: Discussionmentioning

confidence: 99%

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Highly‐expressed P2X7 receptor promotes growth and metastasis of human HOS/MNNG osteosarcoma cells via PI3K/Akt/GSK3β/β‐catenin and mTOR/HIF1α/VEGF signaling

Zhang

Cheng

et al. 2019

Intl Journal of Cancer

121

142

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The P2X7 receptor, an ATP‐gated ion channel, is critical for cancer cell growth, invasiveness, and angiogenesis. Previous studies indicate that P2X7 regulates osteoblast proliferation and osteodeposition and that high P2X7 expression has a pro‐growth effect in osteosarcoma. However, how it functions in osteosarcoma cell growth and metastasis is not clear. Thus, we elucidated molecular mechanisms of P2X7‐dependent positive regulation of osteosarcoma cell proliferation, invasion, migration, epithelial to mesenchymal transition (EMT), and angiogenesis using in vitro and in vivo models. We confirm that P2X7 is highly‐expressed in human osteosarcoma tumor tissues and HOS/MNNG, MG63, U2OS, SW1353 and SAOS‐2 cell lines. P2X7 receptor stimulation enhanced HOS/MNNG and SAOS‐2 cell proliferation, migration and invasion; but knockdown of P2X7 expression or receptor inhibition had opposite effects. P2X7 positively regulated glycogen content, epithelial to mesenchymal transition and stemness of HOS/MNNG cells. P2X7 activation promoted PI3K/Akt/GSK3β/β‐catenin and mTOR/HIF1α/VEGF signaling, thereby mediating pro‐tumor effects of osteosarcoma cells. Consistent with data from in vitro experiments, systemic administration of P2X7 agonist induced tumor growth, metastasis and tumor‐associated bone destruction in osteosarcoma‐bearing nude mice, whereas a P2X7 antagonist reversed these effects. Thus, the P2X7 receptor participates in regulation of osteosarcoma growth and metastasis and we offer evidence that P2X7 may be a promising therapeutic target for treating osteosarcoma.

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“…Previous studies indicate that stimulating EMT and increasing CSCs can promote cancer metastasis and relapse . Cells undergoing EMT are known to acquire stem cell‐like properties.…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Highly‐expressed P2X7 receptor promotes growth and metastasis of human HOS/MNNG osteosarcoma cells via PI3K/Akt/GSK3β/β‐catenin and mTOR/HIF1α/VEGF signaling

Zhang

Cheng

et al. 2019

Intl Journal of Cancer

121

142

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“…The characteristic features of EMT are the decreased expression of the cell adhesion molecule, E-cadherin (E-Cad), and the enhanced expression of the mesenchymal marker, Vimentin (VIM) [19,20]. Previous studies have demonstrated that EMT is a vital process in tumor progression and metastasis, and is associated with a poor prognosis and tumor aggressiveness in several human epithelial cancers, including GC [21][22][23][24]. The identification of factors that induce EMT would greatly contribute to understanding the mechanisms of invasion and metastasis in GC, and may aid the development of effective approaches for the prevention and therapy of this malignancy.…”

Section: Ivyspringmentioning

confidence: 99%

Sonic Hedgehog/Gli1 Signaling Pathway Regulates Cell Migration and Invasion via Induction of Epithelial-to-mesenchymal Transition in Gastric Cancer

Ke¹,

Wang²,

Liu³

et al. 2020

J. Cancer

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Background:The aberrant activation of the Sonic hedgehog (Shh) signaling pathway is involved in progression of several types of cancer, including gastric cancer (GC). However, it remains uncertain whether it also plays a critical role in promoting cancer initiation and progression by inducing epithelial-to-mesenchymal transition (EMT) in GC. Thus, the aim of the present study was to determine whether the Shh pathway is involved in GC, and to investigate the function of the Shh pathway in the induction of EMT in GC. Materials and methods: The expression levels of Shh pathway members and EMT markers were examined in GC tissues by immunohistochemistry. The association between these factors and patient clinicopathological characteristics was analyzed. In addition, Gli-antagonist 61 (GANT61) was used to block Shh/Gli1 pathway activity, and recombinant Shh proteins (N-Shh) were used to activate the Shh pathway in GC cells. Wound healing and Transwell invasion and migration assays were performed to assess the effects of the Shh pathway on the migration and invasion of GC cells in vitro. Furthermore, western blot analysis was used to examine the changes in protein expression. Results: The results demonstrated that these Shh/Gli1 pathway members were upregulated in GC tissues, and that Gli1 upregulation was associated with tumor progression and a poor prognosis. Gli1 expression was negatively associated with E-cadherin (E-Cad) expression, and positively with Vimentin (VIM) expression in GC specimens. Further analysis revealed that when the Shh/Gli1 pathway was activated, the migratory and invasive abilities of GC cells were enhanced, and the expression levels of Gli1 and VIM were increased, while E-Cad expression was decreased. Opposite results were observed when the Shh/Gli1 pathway was blocked by GANT61. Conclusions: The present study indicated that the Shh/Gli1 pathway exhibits an abnormal activation pattern in GC with possible predictive and prognostic significance. The Shh/Gli1 pathway may promote the migratory and invasive potential of GC cells by inducing EMT. The Shh/Gli1 pathway can thus be considered as a potential therapeutic target for GC.

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“…This may be related to the fact that PanCk demonstrates all the epithelial cell clusters (including necrotic fragments), whereas ITGB4 is more specific for invasive cells (when present in small cell clusters) and is involved in EMT , a phenomenon to which tumour budding is at least partly related . For this reason, it is tempting to hypothesise that biomarkers linked with EMT, which have also shown correlation with survival , might be relevant additional markers of tumour budding in challenging tumour specimens.…”

Section: Discussionmentioning

confidence: 99%

“…Slik et al present in small cell clusters) and is involved in EMT [34], a phenomenon to which tumour budding is at least partly related [4]. For this reason, it is tempting to hypothesise that biomarkers linked with EMT, which have also shown correlation with survival [35], might be relevant additional markers of tumour budding in challenging tumour specimens. EMT is a phenomenon consisting of loss or aberrant expression of adherence junction E-cadherin, disintegration of tight junctions (ZO-1), and of basement membranes (ITGB4).…”

mentioning

confidence: 99%

Combined epithelial marker analysis of tumour budding in stage II colorectal cancer

Slik

Blom

Turkki

et al. 2018

The Journal of Pathology CR

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Tumour budding predicts survival of stage II colorectal cancer (CRC) and has been suggested to be associated with epithelial‐to‐mesenchymal transition (EMT). However, the underlying molecular changes of tumour budding remain poorly understood. Here, we performed multiplex immunohistochemistry (mIHC) to phenotypically profile tumours using known EMT‐associated markers: E‐cadherin (adherence junctions), integrin β4 (ITGB4; basement membrane), ZO‐1 (tight junctions), and pan‐cytokeratin. A subpopulation of patients showed high ITGB4 expression in tumour buds, and this coincided with a switch of ITGB4 localisation from the basal membrane of intact epithelium to the cytoplasm of budding cells. Digital image analysis demonstrated that tumour budding with high ITGB4 expression in tissue microarray (TMA) cores correlated with tumour budding assessed from haematoxylin and eosin (H&E) whole sections and independently predicted poor disease‐specific survival in two independent stage II CRC cohorts (hazard ratio [HR] = 4.50 (95% confidence interval [CI] = 1.50–13.5), n = 232; HR = 3.52 (95% CI = 1.30–9.53), n = 72). Furthermore, digitally obtained ITGB4‐high bud count in random TMA cores was better associated with survival outcome than visual tumour bud count in corresponding H&E‐stained samples. In summary, the mIHC‐based phenotypic profiling of human tumour tissue shows strong potential for the molecular characterisation of tumour biology and for the discovery of novel prognostic biomarkers.

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A novel tumor‐based epithelial‐to‐mesenchymal transition score that associates with prognosis and metastasis in patients with Stage II/III colorectal cancer

Cited by 30 publications

References 36 publications

Highly‐expressed P2X7 receptor promotes growth and metastasis of human HOS/MNNG osteosarcoma cells via PI3K/Akt/GSK3β/β‐catenin and mTOR/HIF1α/VEGF signaling

Highly‐expressed P2X7 receptor promotes growth and metastasis of human HOS/MNNG osteosarcoma cells via PI3K/Akt/GSK3β/β‐catenin and mTOR/HIF1α/VEGF signaling

Sonic Hedgehog/Gli1 Signaling Pathway Regulates Cell Migration and Invasion via Induction of Epithelial-to-mesenchymal Transition in Gastric Cancer

Combined epithelial marker analysis of tumour budding in stage II colorectal cancer

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