Epidermal Growth Factor Receptor (EGFR) Is Overexpressed in High-Grade Dysplasia and Adenocarcinoma of the Esophagus and May Represent a Biomarker of Histological Progression in Barrett's Esophagus (BE)

Cronin, James G.; McAdam, Elizabeth; Danikas, Antonios; Tselepis, Chris; Griffiths, Paul; Baxter, J. N.; Thomas, Linzi; Manson, James; Jenkins, Gareth

doi:10.1038/ajg.2010.433

Cited by 75 publications

(56 citation statements)

References 34 publications

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“…While EGFR upregulation on cancer cells has been well documented (6,11,13,26), EGFR upregulation on stromal cells has not been studied and may deserve closer attention as a potential target of anti-cancer therapies. The present study supports the notion that TNF-␣ utilizes EGFR signaling to mediate physiologic effects and raises the possibility that targeted inhibition of one pathway may influence the biologic function of the other.…”

Section: Discussionmentioning

confidence: 99%

TNF-α induces upregulation of EGFR expression and signaling in human colonic myofibroblasts

Yoo

Perez

Nie

et al. 2012

American Journal of Physiology-Gastrointestinal and Liver Physi

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The myofibroblast has recently been identified as an important mediator of tumor necrosis factor-α (TNF-α)-associated colitis and cancer, but the mechanism(s) involved remains incompletely understood. Recent evidence suggests that TNF-α is a central regulator of multiple inflammatory signaling cascades. One important target of TNF-α may be the signaling pathway downstream of the epidermal growth factor receptor (EGFR), which has been associated with many human cancers. Here, we show that long-term exposure of 18Co cells, a model of human colonic myofibroblasts, with TNF-α led to a striking increase in cell surface EGFR expression, an effect that was completely inhibited by cycloheximide. Subsequent EGFR binding by EGF and heparin binding (HB)-EGF was associated with enhanced EGFR tyrosine kinase activity, prolonged ERK activation, and a significant increase in cyclooxygenase-2 (COX-2) expression compared with 18Co cells treated with EGF and HB-EGF alone. TNF-α also increased EGFR expression and signaling in primary myofibroblasts isolated from human colon tissue. TNF-α-induced upregulation of EGFR may be a plausible mechanism to explain the exaggerated cellular responsiveness that characterizes inflammatory bowel disease and that may contribute to a microenvironment that predisposes to colitis-associated cancer through enhanced COX-2 expression.

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Section: Discussionmentioning

confidence: 99%

TNF-α induces upregulation of EGFR expression and signaling in human colonic myofibroblasts

Yoo

Perez

Nie

et al. 2012

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…EGFR is a protein ty- rosine kinase that is overexpressed in a number of malignancies, including 32%-80% of esophageal adenocarcinomas [7,8] and up to 80% of esophageal squamous cell carcinomas [9]. EGFR overexpression is associated with more advanced disease and a worse prognosis in patients with esophageal adenocarcinoma [8] and squamous cell carcinoma [9].…”

Section: Introductionmentioning

confidence: 99%

Preoperative Cetuximab, Irinotecan, Cisplatin, and Radiation Therapy for Patients With Locally Advanced Esophageal Cancer

Lee

Mamon

Hong³

et al. 2013

The Oncologist

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Purpose. To determine the efficacy and toxicity of weekly neoadjuvant cetuximab combined with irinotecan, cisplatin, and radiation therapy in patients with locally advanced esophageal or gastroesophageal junction cancer. Methods and Materials. Patients with stage IIA-IVA esophageal or gastroesophageal junction cancer were enrolled in a Simon's two-stage phase II study. Patients received weekly cetuximab on weeks 0 -8 and irinotecan and cisplatin on weeks 1, 2, 4, and 5, with concurrent radiotherapy (50.4 Gy on weeks 1-6), followed by surgical resection. Results. In the first stage, 17 patients were enrolled, 16 of whom had adenocarcinoma. Because of a low pathologic complete response (pCR) rate in this cohort, the trial was discontinued for patients with adenocarcinoma but squamous cell carcinoma patients continued to be enrolled; two additional patients were enrolled before the study was closed as a result of poor accrual. Of the 19 patients enrolled, 18 patients proceeded to surgery, and 16 patients underwent an R0 resection. Three patients (16%) had a pCR. The median progressionfree survival interval was 10 months, and the median overall survival duration was 31 months. Severe neutropenia occurred in 47% of patients, and severe diarrhea occurred in 47% of patients. One patient died preoperatively from sepsis, and one patient died prior to hospital discharge following surgical resection. Conclusions. This schedule of cetuximab in combination with irinotecan, cisplatin, and radiation therapy was toxic and did not achieve a sufficient pCR rate in patients with localized esophageal adenocarcinoma to undergo further evaluation. The Oncologist 2013;18:281-287 Implications for Practice: Multimodality therapy, involving chemotherapy, radiotherapy, and surgery, has emerged as a standard treatment for locally advanced esophageal cancer. Prognosis with existing therapy for esophageal cancer remains poor, with a 5-year survival rate of only 20% for locally advanced disease. Targeted therapies, such as EGFR inhibitors, are being evaluated for the treatment of locally advanced esophageal cancer, but remain investigational, with a number of ongoing randomized trials exploring the efficacy of various targeted therapies. This study showed that adding the EGFR inhibitor cetuximab to a preoperative chemoradiation regimen of irinotecan, cisplatin, and radiation therapy did not significantly improve rates of pathologic complete response at the time of surgery, and caused substantial toxicity.

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“…In addition, it would also be expressed on the luminal epithelial surface so as to be readily visualized during endoscopy, and be available for biopsy targeting. One recent study evaluated this potential dual role for EGFR using tissue microarray technology, exploring the possibility of EGFR as a relevant biomarker to monitor histological progression, and ultimately to allow for biopsy targeting of abnormal tissue (Cronin et al, 2011). The study showed a stepwise increase in EGFR abundance in BE, high-grade dysplasia, and EAC.…”

Section: Growth Factorsmentioning

confidence: 99%

Gastroesophageal Reflux Disease: Molecular Predictors in Neoplastic Progression of Barrett's Esophagus

François¹,

Khan²,

Yang³

et al. 2012

Gastroesophageal Reflux Disease

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Epidermal Growth Factor Receptor (EGFR) Is Overexpressed in High-Grade Dysplasia and Adenocarcinoma of the Esophagus and May Represent a Biomarker of Histological Progression in Barrett's Esophagus (BE)

Cited by 75 publications

References 34 publications

TNF-α induces upregulation of EGFR expression and signaling in human colonic myofibroblasts

TNF-α induces upregulation of EGFR expression and signaling in human colonic myofibroblasts

Preoperative Cetuximab, Irinotecan, Cisplatin, and Radiation Therapy for Patients With Locally Advanced Esophageal Cancer

Gastroesophageal Reflux Disease: Molecular Predictors in Neoplastic Progression of Barrett's Esophagus

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