Epithelial to Mesenchymal Transition Is a Determinant of Sensitivity to Chemoradiotherapy in Non-Small Cell Lung Cancer

Shintani, Yasushi; Okimura, Akira; Sato, Kazuo; Nakagiri, Tomoyuki; Kadota, Yoshihisa; Inoue, Mitsuru; Sawabata, Noriyoshi; Minami, Masato; Ikeda, Naoki; Kawahara, K; Matsumoto, Tomoshige; Matsuura, Nariaki; Ohta, Mitsunori; Okumura, Meinoshin

doi:10.1016/j.athoracsur.2011.07.032

Cited by 145 publications

(117 citation statements)

References 28 publications

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“…The alkylating chemotherapeutic agent cisplatin, for instance, can induce EMT and confer resistance to subsequent gefitinib treatment (34). In reflection of the EMT interchangeability, Shintani et al reported that a change towards a mesenchymal status during chemotherapy and radiation treatment was correlated with a lower disease free survival rate (35). Hence, the process and evolution of EMT in initial lines of treatment may be important for predicting the response to subsequent treatment such as EGFR-TKIs.…”

Section: Emt and Treatment Response To Egfr-tkismentioning

confidence: 99%

The role of epithelial to mesenchymal transition in resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer

Jakobsen

Demuth

Sørensen³

et al. 2016

Transl. Lung Cancer Res.

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Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) and resistance to lung cancer therapy Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related death worldwide. The 5-year survival remains at 10-15% despite advances in treatment options.Erlotinib, a TKI targeting EGFR, was initially explored as a second-line treatment in NSCLC patients progressing on standard chemotherapy. Survival was prolonged compared to placebo (1). However, erlotinib was soon discovered to be especially efficient in patients with a mutation in the tyrosine kinase domain of EGFR. These patients are nowThe role of epithelial to mesenchymal transition in resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer Correspondence to: Anders Lade Nielsen. Department of Biomedicine, Bartholin Building, Aarhus University, DK-8000, Aarhus C, Denmark.Email: aln@biomed.au.dk.Abstract: Inhibition of the epidermal growth factor receptor (EGFR) is an important strategy when treating non-small cell lung cancer (NSCLC) patients. However, intrinsic resistance or development of resistance during the course of treatment constitutes a major challenge. The knowledge on EGFRdirected tyrosine kinase inhibitors (TKIs) and their biological effect keeps increasing. Within the group of patients with EGFR mutations some benefit to a much higher degree than others, and for patients lacking EGFR mutations a subset experience an effect. Up to 70% of patients with EGFR mutations and 10-20% of patients without EGFR mutations initially respond to the EGFR-TKI erlotinib, but there is a severe absence of good prognostic markers. Despite initial effect, all patients acquire resistance to EGFR-TKIs.Multiple mechanisms have implications in resistance development, but much is still to be explored. Epithelial to mesenchymal transition (EMT) is a transcriptionally regulated phenotypic shift rendering cells more invasive and migratory. Within the EMT process lays a need for external or internal stimuli to give rise to changes in central signaling pathways. Expression of mesenchymal markers correlates to a bad prognosis and an inferior response to EGFR-TKIs in NSCLC due to the contribution to a resistant phenotype. A deeper understanding of the role of EMT in NSCLC and especially in EGFR-TKI resistance-development constitute one opportunity to improve the benefit of TKI treatment for the individual patient. Many scientific studies have linked the EMT process to EGFR-TKI resistance in NSCLC and our aim is to review the role of EMT in both intrinsic and acquired resistance to EGFR-TKIs.Keywords: Epidermal growth factor receptor (EGFR); epithelial to mesenchymal transition (EMT); non-small cell lung cancer (NSCLC); tyrosine kinase inhibitor (TKI)

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Section: Emt and Treatment Response To Egfr-tkismentioning

confidence: 99%

The role of epithelial to mesenchymal transition in resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer

Jakobsen

Demuth

Sørensen³

et al. 2016

Transl. Lung Cancer Res.

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“…However, due to development of resistance to chemo-or radiotherapy, the prognosis of patients with LAD still remains poor. Chemotherapy-or radiotherapyinduced epithelial-to-mesenchymal transition (EMT) in tumor cells has been linked to chemo-or radiotherapeutic resistance (3)(4)(5). Therefore, a better understanding of the nature of chemoradiotherapy resistance and the molecular mechanisms that govern chemotherapy-induced EMT in LAD could lead to exploration of novel molecular targets.…”

Section: Introductionmentioning

confidence: 99%

Let-7c Governs the Acquisition of Chemo- or Radioresistance and Epithelial-to-Mesenchymal Transition Phenotypes in Docetaxel-Resistant Lung Adenocarcinoma

Cui

Huang

Chen

et al. 2013

Molecular Cancer Research

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MicroRNA (miRNA) expression and functions have been reported to contribute to phenotypic features of tumor cells. Although targets and functional roles for many miRNAs have been described in lung adenocarcinoma (LAD), their pathophysiologic roles in phenotypes of chemoresistant LAD cells are still largely unclear. Previously, docetaxel (DTX)-resistant LAD cell lines (SPC-A1/DTX and H1299/DTX) were established by our laboratory and displayed chemo-or radioresistance and mesenchymal features with enhanced invasiveness and motility. Unbiased miRNA profiling indicated that let-7c (MIRLET7C) was significantly downregulated in SPC-A1/DTX cells. Ectopic let-7c expression increased the in vitro and in vivo chemo-or radiosensitivity of DTX-resistant LAD cells through enhanced apoptosis, reversal of epithelial-tomesenchymal phenotypes, and inhibition of in vivo metastatic potential via inactivation of Akt phosphorylation, whereas a let-7c inhibitor decreased the chemo

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“…In addition, increased evidence of EMT was detected in surgically resected specimens following radiotherapy compared with biopsy specimens prior to radiation treatment (66). The patients with EMT marker-positive tumors were associated with a decreased disease-free survival rate compared with those with EMT marker-negative tumors (67). It was concluded that the TGFB1 signaling pathway was associated with insensitivity to radiotherapy due to EMT induction (67).…”

Section: Tgfb1 Exposure Results In Emt and The Inhibition Of Growth Amentioning

confidence: 90%

“…2) (67). Yasushi et al (67) evaluated the association between EMT and radiotherapy sensitivity using NSCLC cells induced to undergo EMT with TGFB1. The expression of EMT markers in tumor specimens obtained from patients with lung cancer were immunohistochemically analyzed.…”

Section: Tgfb1 Exposure Results In Emt and The Inhibition Of Growth Amentioning

confidence: 99%

“…In normal lung cells: ROS are produced following exposure to radiation; ROS subsequently activate the TGF-β1 signaling pathway and stimulate TGF-β1 secretion into the plasma, a potential risk factor for radiation-induced lung injury (47). In lung cancer cells: Regulation of the expression of certain miRs follows TGF-β1 signaling pathway activation; the TGF-β1 signaling molecules diffuse to and activate bystander cells (61); miR-183 may transcriptionally be regulated by the TGF-β1 signaling pathway to silence NK cells by repressing DAP12 transcription, which is critical for surface NK receptor stabilization and downstream signal transduction (62); TGF-β1 exposure induces EMT and radiotherapy resistance (67). TGF-β, transforming growth factor β; EMT, epithelial-mesenchymal transition; NK, natural killer; ROS, reactive oxygen species; RP, radiation pneumonitis; I-SMAD, inhibitory SMAD; SBE, SMAD binding element; P, phosphorylated; miR, microRNA.…”

Section: Predictive Function Of Tgfb1 In Lung Cancer Radiotherapymentioning

confidence: 99%

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Advances in targeting the transforming growth factor β1 signaling pathway in lung cancer radiotherapy (Review)

Tang

Luo

et al. 2017

Oncol Lett

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Abstract. Lung cancer was demonstrated to be the most lethal type of malignant tumor amongst humans in the global cancer statistics of 2012. As one of the primary treatments, radiotherapy has been reported to induce remission in, and even cure, patients with lung cancer. However, the side effects of radiotherapy may prove lethal in certain patients. In past decades, the transforming growth factor β1 (TGFB1) signaling pathway has been revealed to serve multiple functions in the control of lung cancer progression and the radiotherapy response. In mammals, this signaling pathway is initiated through activation of the TGFB1 receptor complex, which signals via cytoplasmic SMAD proteins or other downstream signaling pathways. Multiple studies have demonstrated that TGFB1 serves important functions in lung cancer radiotherapy. The present study summarized and reviewed recent progress in elucidating the function of the TGFB1 signaling pathway in predicting radiation pneumonitis, as well as current strategies for targeting the TGFB1 signaling pathway in lung cancer radiotherapy, which may provide potential targets for lung cancer therapy.

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Epithelial to Mesenchymal Transition Is a Determinant of Sensitivity to Chemoradiotherapy in Non-Small Cell Lung Cancer

Cited by 145 publications

References 28 publications

The role of epithelial to mesenchymal transition in resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer

The role of epithelial to mesenchymal transition in resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer

Let-7c Governs the Acquisition of Chemo- or Radioresistance and Epithelial-to-Mesenchymal Transition Phenotypes in Docetaxel-Resistant Lung Adenocarcinoma

Advances in targeting the transforming growth factor β1 signaling pathway in lung cancer radiotherapy (Review)

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