Abstract
BackgroundEpidermal growth factor receptor (EGFR) is suggested to predict the radiosensitivity and/or prognosis of human esophageal squamous cell carcinoma (ESCC). The objective of this study was to investigate the efficacy of Nimotuzumab (an anti-EGFR monoclonal antibody) on ESCC radiotherapy (RT) and underlying mechanisms.MethodsNimotuzumab was administrated to 2 ESCC cell lines KYSE30 and TE-1 treated with RT. Cell growth, colony formation and apoptosis were used to measure anti-proliferation effects. The method of RNA interference was used to investigate the role of insulin-like growth factor binding protein-3 (IGFBP-3) in ESCC cells radiosensitivity treated with Nimotuzumab. In vivo effect of Nimotuzumab on ESCC radiotherapy was done using a mouse xenograft model.ResultsNimotuzumab enhanced radiation response of KYSE30 cells (with high EGFR expression) in vitro, as evidenced by increased radiation-inhibited cell growth and colony formation and radiation-mediated apoptosis. Mechanism study revealed that Nimotuzumab inhibited phosphorylated EGFR (p-EGFR) induced by EGF in KYSE30 cells. In addition, knockdown of IGFBP-3 by short hairpin RNA significantly reduced KYSE30 cells radiosensitivity (P<0.05), and even after the administration of Nimotuzumab, the RT response of IGFBP-3 silenced KYSE30 cells was not enhanced (P>0.05). In KYSE30 cell xenografts, Nimotuzumab combined with radiation led to significant tumor growth delay, compared with that of radiation alone (P=0.029), and also with IGFBP-3 up-regulation in tumor tissue.ConclusionsNimotuzumab could enhance the RT effect of ESCC cells with a functional active EGFR pathway. In particular, the increased ESCC radiosensitivity by Nimotuzumab might be dependent on the up-regulation of IGFBP-3 through EGFR-dependent pathway.
Highlights
Esophageal cancer is an aggressive cancer constituting the sixth cause of cancer-related deaths worldwide [1]
We found that Nimotuzumab was not toxic to either KYSE30 or TE-1 cell line, even when they were treated with 200 μg/mL of Nimotuzumab for 72 hours (P > 0.05), as determined by the MTT assay (Additional file 1: Figure S1)
The results showed that compared to treatment with RT alone, combination of RT and Nimotuzumab resulted in a significant higher level of cell death in KYSE30 cells (P = 0.01; Additional file 2: Figure S2A), but not significant in TE-1 cells
Summary
Esophageal cancer is an aggressive cancer constituting the sixth cause of cancer-related deaths worldwide [1]. In preclinical studies involving various cancer models, including ESCC, overexpression of EGFR has been found to contribute to epithelial cell proliferation, differentiation, and migration [4,5] and had an inverse relationship to tumor radiocurability [6,7]. Overexpression of EGFR has been shown to correlate with lower tumor control rates after irradiation in several studies [8,9]. Combination of radiotherapy and EGFR inhibitors was reported to improve local tumor control compared to irradiation alone, but it is true that conflicting results exist [10,11]. Epidermal growth factor receptor (EGFR) is suggested to predict the radiosensitivity and/or prognosis of human esophageal squamous cell carcinoma (ESCC). The objective of this study was to investigate the efficacy of Nimotuzumab (an anti-EGFR monoclonal antibody) on ESCC radiotherapy (RT) and underlying mechanisms
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