KIRAMS / 남재경, 이윤진*
Abstract
Purpose: Radiation-induced pulmonary fibrosis (RIPF) is a long-term side effect of thoracic radiation therapy. Hypoxia-induced vascular endothelial mesenchymal transition (EndMT) can occur during the development of RIPF. Here, we examined the direct contribution of endothelial HIF-1α (EC-HIF1α) on RIPF.
Methods and materials: An inducible Cre-lox-mediated endothelial Hif1a deletion mouse line was used to evaluate the potential of HIF-1α inhibition to suppress RIPF. To evaluate the effects of a pharmacologic HIF-1α inhibitor on RIPF after image guided radiation therapy (IGRT) for spontaneous lung adenocarcinoma, we generated conditional tdTomato; K-RasG12D; and p53 flox/flox mice to facilitate tracking of tumor cells expressing tdTomato.
Results: We found that vascular endothelial-specific HIF-1α deletion shortly before radiation therapy inhibited the progression of RIPF along with reduced EndMT, whereas prolonged deletion of endothelial HIF-1α before irradiation did not. Moreover, we revealed that postirradiation treatment with the novel HIF-1α inhibitor, 2-methoxyestradiol (2-ME) could efficiently inhibit RIPF and EndMT. In addition, IGRT using primary mouse models of non-small cell lung cancer showed that combined treatment of 2-ME with ablative high-dose radiation therapy efficiently inhibited RIPF and the growth of both multifocal and single tumors, concomitantly reducing radiation-induced EndMT of normal as well as tumor regions.
Conclusion: These results suggest that a negative regulator of HIF-1α-mediated EndMT, such as 2-ME, may serve as a promising inhibitor of RIPF in radiation therapy.
Affiliations
Jae-Kyung Nam 1 , A-Ram Kim 2 , Seo-Hyun Choi 2 , Ji-Hee Kim 1 , Su Chul Han 3 , Seungwoo Park 3 , Yong Jin Lee 4 , Joon Kim 5 , Jaeho Cho 6 , Hae-June Lee 2 , Yoon-Jin Lee 7
1 Division of Radiation Biomedical Research, Korea Institute of Radiologic and Medical Sciences, Seoul, Korea; Division of Applied RI, Korea Institute of Radiologic and Medical Sciences, Seoul, Korea.
2 Division of Radiation Biomedical Research, Korea Institute of Radiologic and Medical Sciences, Seoul, Korea.
3 Comprehensive Radiation Irradiation Center, Korea Institute of Radiologic and Medical Sciences, Seoul, Korea.
4 Laboratory of Biochemistry, Division of Life Sciences, Korea University, Seoul, Korea.
5 Division of Applied RI, Korea Institute of Radiologic and Medical Sciences, Seoul, Korea.
6 Department of Radiation Oncology, Yonsei University College of Medicine, Seoul, Korea.
7 Division of Radiation Biomedical Research, Korea Institute of Radiologic and Medical Sciences, Seoul, Korea. Electronic address: yjlee8@kirams.re.kr.
편집위원
방사선유도 폐섬유증(RIPF)은 흉부 방사선 치료의 long-term side effect이며, 발병과정에서 EndMT가 일어나는 것으로 알려졌다. 본 연구에서는 EC-HIF1α와 RIPF의 직접적인 상관관계를 규명하고자 했다. 본 연구를 통해 방사선 치료 직전의 endothelial-specific HIF-1α deletion과 2-ME와 같은 HIF-1α inhibitor를 상용하여 RIPF와 EndMT를 제어할 수 있음을 밝힘으로써, 방사선 치료과정에서 발생하는 폐섬유증의 치료 대안을 제시하였다.
2021-03-30 11:36:36