Epithelial–mesenchymal-transition induced by EGFR activation interferes with cell migration and response to irradiation and cetuximab in head and neck cancer cells

Holz, Carmen; Niehr, Franziska; Boyko, Mariya M; Hristozova, Tsvetana; Distel, Luitpold; Budach, Volker; Tinhofer, Ingeborg

doi:10.1016/j.radonc.2011.05.042

Cited by 72 publications

(63 citation statements)

References 37 publications

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“…Although separate EMT genes like fibronectin 1, Snail, Slug, and E-cadherin have already been associated with radioresistance (37)(38)(39)(40), it has not been clarified why EMT would cause radioresistance. We hypothesize that simultaneous with acquiring a mesenchymal phenotype, the mechanisms by which cells can become more resistant to irradiation are altered.…”

Section: Discussionmentioning

confidence: 99%

Pretreatment microRNA Expression Impacting on Epithelial-to-Mesenchymal Transition Predicts Intrinsic Radiosensitivity in Head and Neck Cancer Cell Lines and Patients

Jong

Hoeve

Grénman

et al. 2015

Clinical Cancer Research

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Purpose: Predominant causes of head and neck cancer recurrence after radiotherapy are rapid repopulation, hypoxia, fraction of cancer stem cells, and intrinsic radioresistance. Currently, intrinsic radioresistance can only be assessed by ex vivo colony assays. Besides being time-consuming, colony assays do not identify causes of intrinsic resistance. We aimed to identify a biomarker for intrinsic radioresistance to be used before start of treatment and to reveal biologic processes that could be targeted to overcome intrinsic resistance.Experimental Design: We analyzed both microRNA and mRNA expression in a large panel of head and neck squamous cell carcinoma (HNSCC) cell lines. Expression was measured on both irradiated and unirradiated samples. Results were validated using modified cell lines and a series of patients with laryngeal cancer.Results: miRs, mRNAs, and gene sets that correlated with resistance could be identified from expression data of unirradiated cells. The presence of epithelial-to-mesenchymal transition (EMT) and low expression of miRs involved in the inhibition of EMT were important radioresistance determinants. This finding was validated in two independent cell line pairs, in which the induction of EMT reduced radiosensitivity. Moreover, low expression of the most important miR (miR-203) was shown to correlate with local disease recurrence after radiotherapy in a series of patients with laryngeal cancer.Conclusions: These findings indicate that EMT and low expression of EMT-inhibiting miRs, especially miR-203, measured in pretreatment material, causes intrinsic radioresistance of HNSCC, which could enable identification and treatment modification of radioresistant tumors.

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Section: Discussionmentioning

confidence: 99%

Pretreatment microRNA Expression Impacting on Epithelial-to-Mesenchymal Transition Predicts Intrinsic Radiosensitivity in Head and Neck Cancer Cell Lines and Patients

Jong

Hoeve

Grénman

et al. 2015

Clinical Cancer Research

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“…In a study by Thomson et al (34), non-smallcell lung carcinoma cells were differentially sensitive to the EGFR inhibitor erlotinib, and EMT status was a key determinant of sensitivity to treatment. Overexpression of the EGFR occurs in many tumors, including ovarian cancer, and is associated with increased aggressiveness and invasiveness, as well as the induction of EMT (22,(77)(78)(79). Several studies have identified the EGFR as an independent prognostic indicator for poor outcomes (20,80), although the clinical consequences of EGFR expression remain controversial (23,24,81).…”

Section: Discussionmentioning

confidence: 99%

Flow induces epithelial-mesenchymal transition, cellular heterogeneity and biomarker modulation in 3D ovarian cancer nodules

Rizvi

Gürkan

Tasoğlu

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

215

229

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Seventy-five percent of patients with epithelial ovarian cancer present with advanced-stage disease that is extensively disseminated intraperitoneally and prognosticates the poorest outcomes. Primarily metastatic within the abdominal cavity, ovarian carcinomas initially spread to adjacent organs by direct extension and then disseminate via the transcoelomic route to distant sites. Natural fluidic streams of malignant ascites triggered by physiological factors, including gravity and negative subdiaphragmatic pressure, carry metastatic cells throughout the peritoneum. We investigated the role of fluidic forces as modulators of metastatic cancer biology in a customizable microfluidic platform using 3D ovarian cancer nodules. Changes in the morphological, genetic, and protein profiles of biomarkers associated with aggressive disease were evaluated in the 3D cultures grown under controlled and continuous laminar flow. A modulation of biomarker expression and tumor morphology consistent with increased epithelial-mesenchymal transition, a critical step in metastatic progression and an indicator of aggressive disease, is observed because of hydrodynamic forces. The increase in epithelial-mesenchymal transition is driven in part by a posttranslational up-regulation of epidermal growth factor receptor (EGFR) expression and activation, which is associated with the worst prognosis in ovarian cancer. A flowinduced, transcriptionally regulated decrease in E-cadherin protein expression and a simultaneous increase in vimentin is observed, indicating increased metastatic potential. These findings demonstrate that fluidic streams induce a motile and aggressive tumor phenotype. The microfluidic platform developed here potentially provides a flow-informed framework complementary to conventional mechanism-based therapeutic strategies, with broad applicability to other lethal malignancies.tumor microenvironment | stress response | molecular targets | combination therapies | photodynamic therapy C ancer metastases are responsible for 90% of cancer-related deaths, but the biological and physical factors that determine the fate and heterogeneity of metastatic tumors remain poorly understood (1-6). Ovarian cancer is the leading cause of deaths related to gynecologic malignancies, and is frequently diagnosed at an advanced stage. Initially, ovarian cancer metastasizes by direct extension to sites that are proximal to the primary tumor through a complex series of events including migration, assembly, and proliferation (7-10). Dissemination to distant sites prognosticates the poorest outcomes for ovarian cancer patients and occurs via transcoelomic, lymphatic, or hematogenous routes (7,9,10). Among these routes, transcoelomic metastases are the most frequent and are responsible for the highest morbidity and mortality rates, which in turn are associated with the frequent production of malignant ascites (7, 9, 10). Under normal physiologic conditions, the great majority of peritoneal fluid is resorbed by the vasculature and the lymphatics and...

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“…EGFR stimulation induces cell migration through the activation of matrix metalloproteinases (MMPs) (24), signal transducer and activator of transcription 3 (STAT3) (25,26) or the MEK/ERK and PI3K signaling pathways (9), and may be associated with an epithelial-mesenchymal transition (EMT)-like phenotype (27). Furthermore, cross-talk between EGFR and G-protein-coupled receptors contributes to cell migration (28,29).…”

Section: Introductionmentioning

confidence: 99%

Regulation of cell migration via the EGFR signaling pathway in oral squamous cell carcinoma cells

et al. 2016

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Abstract. Cell migration potency is essential in cancer metastasis and is often regulated by extracellular stimuli. Oral squamous cell carcinoma cell lines include those that are sensitive, as well as resistant, to the effects of the epidermal growth factor receptor (EGFR) inhibitor cetuximab on cell migration. In the present study, the molecular differences in the EGFR response to cell migration between the SAS cetuximab-sensitive and HSC4 cetuximab-resistant cell lines was examined. Treatment with the EGFR inhibitors AG1478 and cetuximab reduced the migration potency of SAS cells, but not HSC4 cells. The migration of the two cell lines was inhibited under serum-free culture conditions, and the addition of EGF to the serum-free medium promoted the migration of SAS cells, but not HSC4 cells. In addition, SAS cell migration was reduced by the mitogen-activated protein kinase kinase and protein kinase B (Akt) inhibitors PD98059 and MK2206, whereas HSC4 cell migration was only inhibited by MK2206. EGF induced an increase in extracellular signal-regulated kinase phosphorylation levels in HSC4 cells, and stimulated Akt phosphorylation levels in SAS cells. Furthermore, the staining of actin filaments with phalloidin was significantly increased by the inhibition of EGFR in SAS cells, but was not observed as altered in HSC4 cells. Conversely, the addition of EGF to the culture medium decreased the accumulation of actin filaments in SAS cells. The results suggest that the EGF-EGFR signaling pathway has an important role in SAS cell migration via the modulation of actin dynamics, and that HSC4 cell migration is regulated by a serum component other than EGFR.

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Epithelial–mesenchymal-transition induced by EGFR activation interferes with cell migration and response to irradiation and cetuximab in head and neck cancer cells

Cited by 72 publications

References 37 publications

Pretreatment microRNA Expression Impacting on Epithelial-to-Mesenchymal Transition Predicts Intrinsic Radiosensitivity in Head and Neck Cancer Cell Lines and Patients

Pretreatment microRNA Expression Impacting on Epithelial-to-Mesenchymal Transition Predicts Intrinsic Radiosensitivity in Head and Neck Cancer Cell Lines and Patients

Flow induces epithelial-mesenchymal transition, cellular heterogeneity and biomarker modulation in 3D ovarian cancer nodules

Regulation of cell migration via the EGFR signaling pathway in oral squamous cell carcinoma cells

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