Esophageal Adenocarcinoma Cells and Xenograft Tumors Exposed to Erb-b2 Receptor Tyrosine Kinase 2 and 3 Inhibitors Activate Transforming Growth Factor Beta Signaling, Which Induces Epithelial to Mesenchymal Transition

Ebbing, Eva A.; Steins, Anne; Fessler, Evelyn; Stathi, Phylicia; Lesterhuis, W. Joost; Krishnadath, Kausilia K.; Vermeulen, Louis; Medema, Jan Paul; Bijlsma, Maarten F.; Laarhoven, Hanneke W. M. van

doi:10.1053/j.gastro.2017.03.004

Cited by 31 publications

(48 citation statements)

References 45 publications

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“…The cells with EMT are present certain anti-apoptotic activity and drug resistance [89]. The signaling pathways involved in EMT include TGF-β, Wnt, Hedgehog, Notch, ILK, and uPAR (urokinase-type plasminogen activator receptor) [90][91][92][93][94][95]. A recent study has revealed that DADS induces the reversal of the EMT and inhibits cell growth by inactivating the β-catenin signaling pathway in breast cancer cells [96].…”

Section: Inhibition Of Tumor Metastasis By Dadsmentioning

confidence: 99%

The Progress of Diallyl Disulfide in Anti-Cancer

Lz¹,

Liao²,

Wang³

et al. 2017

Chemotherapy

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Considerable evidence in recent years suggests that garlic has anti-proliferative effects on various types of cancer. Garlic contains water-soluble and oil-soluble sulfur compounds. Oil-soluble compounds (OSCs), such as diallyl sulfide (DAS), diallyl disulfide (DADS), diallyl trisulfide (DATS) and ajoene are more effective than watersoluble compounds in protection against cancer. DADS, a major organosulfur compound derived from garlic, can reduce carcinogen-induced cancers in experimental animals and inhibit the proliferation of various types of cancer cells. The mechanisms of these action of DADS include activation of metabolic enzymes that detoxify carcinogens, suppression of the formation of DNA adducts, antioxidant effects, regulation of cell-cycle progression, induction of apoptosis, and inhibition of angiogenesis and metastasis. These topics are discussed in depth in this review.

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Section: Inhibition Of Tumor Metastasis By Dadsmentioning

confidence: 99%

The Progress of Diallyl Disulfide in Anti-Cancer

Lz¹,

Liao²,

Wang³

et al. 2017

Chemotherapy

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“…OE19 cells (ATCC, Manassas, VA) were cultured according to standard procedures as described earlier . Carboplatin and paclitaxel were purchased from the pharmacy of the Academic Medical Center.…”

Section: Methodsmentioning

confidence: 99%

“…The primary EAC cultures used in our study are 031M, 007B, 081R and 037M, and patient characteristics regarding these cultures are listed in Table 1. Primary cultures were maintained as described earlier …”

Section: Methodsmentioning

confidence: 99%

“…Immunofluorescence was performed as previously described . An SP8‐X SMD confocal microscope (Leica, Wetzlar, Germany) was used for visualization.…”

Section: Methodsmentioning

confidence: 99%

“…Importantly, none were targetable by currently available agents. Recently, we identified epithelial‐to‐mesenchymal transition (EMT) as a mechanism of resistance in EAC in response to growth factor inhibition . EMT has been linked to aberrant expression of miRNAs and concomitant upregulation of stemness .…”

Section: Introductionmentioning

confidence: 99%

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Chemoradiation induces epithelial‐to‐mesenchymal transition in esophageal adenocarcinoma

Steins

Ebbing

Creemers

et al. 2019

Intl Journal of Cancer

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Multimodality treatment has advanced the outcome of esophageal adenocarcinoma (EAC), but overall survival remains poor. Therapeutic pressure activates effective resistance mechanisms and we characterized these mechanisms in response to the currently used neoadjuvant treatment against EAC: carboplatin, paclitaxel and radiotherapy. We developed an in vitro approximation of this regimen and applied it to primary patient‐derived cultures. We observed a heterogeneous epithelial‐to‐mesenchymal (EMT) response to the high therapeutic pressure exerted by chemoradiation. We found EMT to be initiated by the autocrine production and response to transforming growth factor beta (TGF‐β) of EAC cells. Inhibition of TGF‐β ligands effectively abolished chemoradiation‐induced EMT. Assessment of TGF‐β serum levels in EAC patients revealed that high levels after neoadjuvant treatment predicted the presence of fluorodeoxyglucose uptake in lymph nodes on the post‐chemoradiation positron emission tomography‐scan. Our study shows that chemoradiation contributes to resistant metastatic disease in EAC patients by inducing EMT via autocrine TGF‐β production. Monitoring TGF‐β serum levels during treatment could identify those patients at risk of developing metastatic disease, and who would likely benefit from TGF‐β targeting therapy.

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SPARC expression in tumor microenvironment induces partial epithelial‐to‐mesenchymal transition of esophageal adenocarcinoma cells via cooperating with TGF‐β signaling

Yan

Bai

et al. 2022

Cell Biology International

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Secreted protein, acidic and rich in cysteine (SPARC) has been characterized as an oncoprotein in esophageal squamous cell carcinoma (ESCC), but its involvement in the pathological development of esophageal adenocarcinoma (ESAD) remains poorly understood. In this study, we aimed to explore the sources of SPARC in the tumor microenvironment (TME) and its functional role in ESAD. Bioinformatic analysis was conducted using data from The Cancer Genome Atlas (TCGA)-esophageal cancer (ESCA) and Genotype-Tissue Expression (GTEx). ESAD tumor cell line OE33 and OE19 cells were used as in vitro cell models. Results showed that SPARC upregulation was associated with unfavorable disease-specific survival (DSS) in ESAD. ESAD tumor cells (OE33 and OE19) had no detectable SPARC protein expression. In contrast, IHC staining in ESAD tumor tissues suggested that peritumoral stromal cells (tumorassociated fibroblasts and macrophages) were the dominant SPARC source in TME. Exogenous SPARC induced partial epithelial-to-mesenchymal transition of ESAD cells, reflected by reduced CDH1 and elevated ZEB1/VIM expression at both mRNA and protein levels. Besides, exogenous SPARC enhanced tumor cell invasion. When TGFBR2 expression was inhibited, the activation of TGF-β signaling induced by exogenous SPARC was impaired. However, the activating effects were rescued by overexpressing mutant TGFBR2 resistant to the shRNA sequence. Copresence of exogenous SPARC and TGF-β1 induced higher expression of mesenchymal markers and enhanced the invading capability of ESAD cells than TGF-β1 alone. In conclusion, this study suggests a potential cross-talk between ESAD tumor stromal cells and cancer cells via a SPARC-TGF-β1 paracrine network.

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Esophageal Adenocarcinoma Cells and Xenograft Tumors Exposed to Erb-b2 Receptor Tyrosine Kinase 2 and 3 Inhibitors Activate Transforming Growth Factor Beta Signaling, Which Induces Epithelial to Mesenchymal Transition

Cited by 31 publications

References 45 publications

The Progress of Diallyl Disulfide in Anti-Cancer

The Progress of Diallyl Disulfide in Anti-Cancer

Chemoradiation induces epithelial‐to‐mesenchymal transition in esophageal adenocarcinoma

SPARC expression in tumor microenvironment induces partial epithelial‐to‐mesenchymal transition of esophageal adenocarcinoma cells via cooperating with TGF‐β signaling

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