KIRAMS / 최서현, 이윤진*
Abstract
It remains controversial whether targeting tumour vasculature can improve radiotherapeutic efficacy. We report that radiation-induced endothelial-to-mesenchymal transition (EndMT) leads to tumour vasculature with abnormal SMA+NG2+ pericyte recruitment during tumour regrowth after radiotherapy. Trp53 (but not Tgfbr2) deletion in endothelial cells (ECs) inhibited radiation-induced EndMT, reducing tumour regrowth and metastases with a high CD44v6+ cancer-stem-cell (CSC) content after radiotherapy. Osteopontin, an EndMT-related angiocrine factor suppressed by EC-Trp53 deletion, stimulated proliferation in dormant CD44v6+ cells in severely hypoxic regions after radiation. Radiation-induced EndMT significantly regulated tumour-associated macrophage (TAM) polarization. CXCR4 upregulation in radioresistant tumour ECs was highly associated with SDF-1+ TAM recruitment and M2 polarization of TAMs, which was suppressed by Trp53 deletion. These EndMT-related phenomena were also observed in irradiated human lung cancer tissues. Our findings suggest that targeting tumour EndMT might enhance radiotherapy efficacy by inhibiting the re-activation of dormant hypoxic CSCs and promoting anti-tumour immune responses.
Author information
Choi SH1,2, Kim AR1, Nam JK1, Kim JM3, Kim JY3, Seo HR4, Lee HJ1, Cho J3, Lee YJ5.
1
Division of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences, Seoul, 139-706, Korea.
2
Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
3
Department of Radiation Oncology, Yonsei University College of Medicine, Seoul, 120-752, Korea.
4
Cancer Biology Research Laboratory, Institute Pasteur Korea, Gyeonggi-do, 13488, Korea.
5
Division of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences, Seoul, 139-706, Korea. yjlee8@kirams.re.kr.