The network of epithelial–mesenchymal transition: potential new targets for tumor resistance

Nantajit, Danupon; Dong, Lin; Li, Jian Jian

doi:10.1007/s00432-014-1840-y

Cited by 123 publications

(122 citation statements)

References 202 publications

(237 reference statements)

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“…Both, Snail and Twist are downstream in signaling pathways activated by TGFβ, integrins, IL‐6, FGF, and HGF 3, 23, 76. In agreement with these findings, we provide evidence that H. pylori ‐induced differentiation and activation of fibroblasts with rise in HGF and TGFβ mRNA expression were accompanied by increase in HGFR, TGFβR, FGFR, Snail, and Twist mRNA expression in RGM‐1 cells.…”

Section: Discussionsupporting

confidence: 86%

Role of Helicobacter pylori infection in cancer‐associated fibroblast‐induced epithelial‐mesenchymal transition in vitro

et al. 2018

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BackgroundMajor human gastrointestinal pathogen Helicobacter pylori (H. pylori) colonizes the gastric mucosa causing inflammation and severe complications including cancer, but the involvement of fibroblasts in the pathogenesis of these disorders in H. pylori‐infected stomach has been little studied. Normal stroma contains few fibroblasts, especially myofibroblasts. Their number rapidly increases in the reactive stroma surrounding inflammatory region and neoplastic tissue; however, the interaction between H. pylori and fibroblasts remains unknown. We determined the effect of coincubation of normal rat gastric fibroblasts with alive H. pylori (cagA+vacA+) and H. pylori (cagA−vacA−) strains on the differentiation of these fibroblasts into cells possessing characteristics of cancer‐associated fibroblasts (CAFs) able to induce epithelial‐mesenchymal transition (EMT) of normal rat gastric epithelial cells (RGM‐1).Materials and MethodsThe panel of CAFs markers mRNA was analyzed in H. pylori (cagA+vacA+)‐infected fibroblasts by RT‐PCR. After insert coculture of differentiated fibroblasts with RGM‐1 cells from 24 up to 48, 72, and 96 hours, the mRNA expression for EMT‐associated genes was analyzed by RT‐PCR.ResultsThe mRNA expression for CAFs markers was significantly increased after 72 hours of infection with H. pylori (cagA+vacA+) but not H. pylori (cagA−vacA−) strain. Following coculture with CAFs, RGM‐1 cells showed significant decrease in E‐cadherin mRNA, and the parallel increase in the expression of Twist and Snail transcription factors mRNA was observed along with the overexpression of mRNAs for TGFβR, HGFR, FGFR, N‐cadherin, vimentin, α‐SMA, VEGF, and integrin‐β1.Conclusion Helicobacter pylori (cagA+vacA+) strain induces differentiation of normal fibroblasts into CAFs, likely to initiate the EMT process in RGM‐1 epithelial cell line.

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Section: Discussionsupporting

confidence: 86%

Role of Helicobacter pylori infection in cancer‐associated fibroblast‐induced epithelial‐mesenchymal transition in vitro

et al. 2018

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“…Hypoxia has been shown to trigger induction of EMT (37) and to generate CSC by hypoxia-induced transcription factors (38,39). Moreover, it has been shown that epithelial cells can gain stem cell properties during EMT (40), facilitating tumorigenic potential and selfrenewal (37).…”

Section: Influences On Treatment Sensitivitymentioning

confidence: 99%

“…The exact mechanism of how the EMT process is induced is not yet clear but one suggestion is that EMT is initiated upon signaling from surrounding tumor stroma cells (44 decreased E-Cadherin expression) and the increase of mesenchymal markers (e.g. increased NCadherin) (37). The loss of E-cadherin is considered a hallmark for EMT and is used as a marker for EMT in head and neck cancer (47).…”

Section: Epithelial-to-mesenchymal Transitionmentioning

confidence: 99%

“…The loss of E-cadherin is considered a hallmark for EMT and is used as a marker for EMT in head and neck cancer (47). Activation of transcription factors such as Snail or Slug, which activate mesenchymal markers and represses epithelial markers, can also be observed and plays an important role for EMT induction (37). EMT has been associated with chemoradio-resistance in several cancers including HNSCC (48,49).…”

Section: Epithelial-to-mesenchymal Transitionmentioning

confidence: 99%

“…EMT has been associated with chemoradio-resistance in several cancers including HNSCC (48,49). The induction of EMT activates genes involved in inhibition of apoptosis and enhancement of cell survival, resulting in cell death evasion and thereby treatment resistance (37). Examples of protein markers that have been associated with treatment resistance and poor prognosis are Twist, Vimentin, Fibronectin, Snail, Slug, FOX1, N-cadherin among others (50-55).…”

Section: Epithelial-to-mesenchymal Transitionmentioning

confidence: 99%

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The impact of Survivin, WRAP53β, and Hypoxia on treatment response in Head and Neck Cancer

Tiefenböck-Hansson¹

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v ABSTRACTSquamous cell carcinoma (SCC) is the most common histological type of cancer in the head and neck region and arises in the epithelial mucosa of the upper aerodigestive tract.Approximately one and a half million people are living with the diagnosis. Despite efforts in prevention and advances in treatment, the 5-year survival rate still lies around 60%, and recurrences and second primary tumors remain a problem. Moreover, treatment responses vary from patient to patient, highlighting the need for individually tailored treatments. To make this possible, biomarkers predicting treatment outcome are needed to better guide treatment decisions.The aim of this thesis was to evaluate the expression of certain proteins and the frequency of certain SNPs (Single nucleotide polymorphisms) in tumor biopsies and cell cultures of head and neck squamous cell carcinomas (HNSCC), and to explore their potential as biomarkers for treatment outcome. Furthermore, we aimed to study the impact of hypoxia on treatment response, epithelial-to-mesenchymal transition (EMT), and induction of cancer stem cells (CSC).In papers I and II, we investigated two proteins, survivin and WRAP53β, using immunohistochemistry (IHC) in tumor biopsies from 40 patients categorized as Nonresponders or Responders to radiotherapy. High expression of survivin and nuclear expression of WRAP53β were significantly more prevalent in the Responder group. The combination of these two factors correlated strongest to overall survival, but not to a significantly higher extent compared to survivin alone. Moreover, when examined separately, a high percentage of p53-stained cells and the presence of the SNP FGFR4 Gln388Arg correlated to improved overall survival, whereas the SNP XPD Lys751Gln was associated with worse overall survival. The latter three showed no significant correlations to radiotherapy response. In paper III, the two ABSTRACT vi most promising proteins identified in papers I and II were analyzed in a study cohort of 149 tumor biopsies of glottic laryngeal SCC, categorized as T2N0-T3N0. In this patient group, no significant associations between survivin expression and survival could be found. However, expression of cytoplasmic WRAP53β was significantly linked to worse disease-free-survival (DSF) compared to nuclear WRAP53β or negative staining for WRAP53β. Positive expression of p16INK4a was found in 7% of the tumors. The prevalence of p16 INK4a was higher in younger patients (<60) and associated with absence of recurrence and longer DSF.In paper IV, five HNSCC cell lines were cultured in normoxic (20% O 2 ) and hypoxic (1% O 2 )conditions and changes in treatment response, EMT profile, and expression of CSC markers were examined. As expected, hypoxia induced EMT and to a certain extent expression of CSC markers. Silencing of the hypoxia-inducible-factor-1α (HIF-1α) only partly reversed these effects, suggesting that other mechanisms are involved. Whereas most cell lines became more resistant to treatment in hypoxia, one cell line (LK0412) ...

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New insights into the role of EMT in tumor immune escape

et al. 2017

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Novel immunotherapy approaches have provided durable remission in a significant number of cancer patients with cancers previously considered rapidly lethal. Nonetheless, the high degree of nonresponders, and in some cases the emergence of resistance in patients who do initially respond, represents a significant challenge in the field of cancer immunotherapy. These issues prompt much more extensive studies to better understand how cancer cells escape immune surveillance and resist immune attacks. Here, we review the current knowledge of how cellular heterogeneity and plasticity could be involved in shaping the tumor microenvironment (TME) and in controlling antitumor immunity. Indeed, recent findings have led to increased interest in the mechanisms by which cancer cells undergoing epithelial‐mesenchymal transition (EMT), or oscillating within the EMT spectrum, might contribute to immune escape through multiple routes. This includes shaping of the TME and decreased susceptibility to immune effector cells. Although much remains to be learned on the mechanisms at play, cancer cell clones with mesenchymal features emerging from the TME seem to be primed to face immune attacks by specialized killer cells of the immune system, the natural killer cells, and the cytotoxic T lymphocytes. Recent studies investigating patient tumors have suggested EMT as a candidate predictive marker to be explored for immunotherapy outcome. Promising data also exist on the potential utility of targeting these cancer cell populations to at least partly overcome such resistance. Research is now underway which may lead to considerable progress in optimization of treatments.

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The network of epithelial–mesenchymal transition: potential new targets for tumor resistance

Cited by 123 publications

References 202 publications

Role of Helicobacter pylori infection in cancer‐associated fibroblast‐induced epithelial‐mesenchymal transition in vitro

Role of Helicobacter pylori infection in cancer‐associated fibroblast‐induced epithelial‐mesenchymal transition in vitro

The impact of Survivin, WRAP53β, and Hypoxia on treatment response in Head and Neck Cancer

New insights into the role of EMT in tumor immune escape

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