Background: Acquired resistance to the Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs), including gefitinib and erlotinib, is a critical issue of lung cancer therapy. Vascular endothelial growth factor C (VEGF-C) promote lymphangiognesis and cancer progression but the detailed mechanism related to EGFR-TKIs resistance and cancer stemness remain mostly unclear. Methods: The expression levels of VEGF-C and SLUG in lung cancer patients with gefitinib responder (n = 41) and gefitinib non-responder (n = 39) were examined by quantitative RT-PCR and Oncomine database analysis. The effect of VEGF-C and SLUG on EGFR-TKIs resistance by MTT assay and cancer-stem-like properties by quantitative RT-PCR in vitro.Results: In this study, we observed that high level of VEGF-C correlated to EGFR mutation-independent gefitinib resistance and cancer-stem-like properties in vitro and in vivo; lung cancer patients with high VEGF-C expression had high level of cancer stem cell markers and worst progression-free survival. Moreover, we found a transcription factor, SLUG, involved in VEGF-C/VEGFR3-induced gefitinib resistance and cancer stemness of lung cancer.Conclusions: These results suggest that VEGF-C is a critical role for EGFR-TKIs resistance and cancer stemness of lung cancer, and targeting VEGF-C/VEGFR3/SLUG pathway may provide a potential therapeutic strategy for lung cancer patient with acquired resistance to EGFR-TKIs.
Date:
2016-04
Relation:
Journal of Thoracic Oncology. 2016 Apr;11(4, Suppl.):S132-133.
