뇌암세포에서 방사선 조사에 의한 Hyaluronan와 CD44의 생성과 그에 따른 침윤성 획득 기전 연구

Abstract

Radiotherapy is widely used as a standard treatment for glioblastoma. However, recent studies have reported that ionizing radiation (IR) paradoxically promotes infiltration of glioma cells to the surrounding brain parenchyma, resulting in relapse after radiotherapy. The diffuse into other brain parenchyma permits the glioma cells to embed deep within the brain, grow into large tumors, and elude early diagnosis. By the time symptoms such as impaired vision and hearing are evident, these tumors have already spread and have caused irreparable damage to the brain. In this study, I attempted to define the molecular signaling mechanisms that are responsible for the side-effect of radiotherapy for glioma treatment. Importantly, I found that fractionated irradiation causes to alter the composition of extracellular matrix (ECM), thereby transforming glioma cells to mesenchymal phenotypes and endowing glioma cells with infiltrative property. Of note, hyaluronic acid (HA), a major component of ECM in brain, was markedly increased by fractionated irradiation. Importantly, fractionated radiation promoted the synthesis of HA by triggering IL-1α-AKT-NF-κB-HAS2 signaling axis. In addition, irradiation also induced the expression of CD44 in glioma cells, the receptor of HA through K-Ras/ERK/β-catenin signaling axis. Notably, CD44 and HA enhanced synergistically the infiltrative property of glioma cells. Collectively, this study suggests that fractionated radiation-induced HA synthesis and CD44 expression causes aberrant interaction of glioma cells with the ECM component in tumor microenvironment, leading to mesenchymal transformation of glioma cells. Combination of radiotherapy and targeting the aberrant interaction may improve therapeutic interventions, dampening the side-effects of radiotherapy in glioma treatment.