Hypo-fractionation radiotherapy normalizes tumor vasculature in non-small cell lung cancer xenografts through the p-STAT3/HIF-1 alpha signaling pathway

Abstract

Background: Hypo-fractionation radiotherapy (HFRT) was considered to be an important treatment for non-small cell lung cancer (NSCLC), but the radiobiological effects of HFRT on NSCLC remain unclear. The aim of this study was to investigate specific biological effect of HFRT on tumor angiogenesis, compared with conventional radiotherapy (CRT). Methods: The subcutaneous xenograft models and the dorsal skinfold window chamber (DSWC) models of nude mice bearing H460 and HCC827 NSCLC cells were irradiated with doses of 0 Gy (sham group), 22 Gy delivered into 11 fractions (CRT group) or 12 Gy delivered into 1 fraction (HFRT group). At certain time-points after irradiation, the volumes, hypoxic area, coverage rate of pericyte and micro-vessel density (MVD) of the subcutaneous xenograft models were detected, and the tumor vasculature was visualized in the DSMC model. The expressions of phosphorylated signal transducer and activator of transcription (p-STAT3), hypoxia-inducible factor 1-α (HIF-1α), CXCL12 and VEGFA were detected. Results: Compared with the CRT groups, HFRT showed more-efficient tumor growth-suppression, accompanied by a HFRT-induced window-period, during which vasculature was normalized, tumor hypoxia was improved and MVD was decreased. Moreover, during the window-period, the signal levels of p-STAT3/HIF-1α pathway and the expressions of its downstream angiogenic factors (VEGFA and CXCL12) were inhibited by HFRT. Conclusion: Compared with CRT, HFRT induced tumor vasculature normalization by rendering the remaining vessels less tortuous and increasing pericyte coverage of tumor blood vessels, thereby ameliorating tumor hypoxia and enhancing the tumor-killing effect. Moreover, HFRT might exert the aforementioned effects through p-STAT3/HIF-1α signaling pathway.