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Tumour-vasculature development via endothelial-to-mesenchymal transition after radiotherapy controls CD44v6+ cancer cell and macrophage polarization

 Seo-Hyun Choi  ;  A-Ram Kim  ;  Jae-Kyung Nam  ;  Jin-Mo Kim  ;  Jee-Youn Kim  ;  Haeng Ran Seo  ;  Hae-June Lee  ;  Jaeho Cho  ;  Yoon-Jin Lee 
 NATURE COMMUNICATIONS, Vol.9(1) : 5108, 2018 
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Animals ; Cell Line, Tumor ; Cell Transdifferentiation/drug effects ; Cell Transdifferentiation/genetics ; Endothelial Cells/metabolism* ; Epithelial-Mesenchymal Transition/genetics ; Epithelial-Mesenchymal Transition/physiology* ; Female ; Heterocyclic Compounds/pharmacology ; Humans ; Hyaluronan Receptors/metabolism* ; Immunohistochemistry ; Macrophages/metabolism* ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Neoplastic Stem Cells/metabolism ; Receptor, Transforming Growth Factor-beta Type II/genetics ; Receptor, Transforming Growth Factor-beta Type II/metabolism ; Receptors, CXCR4/genetics ; Receptors, CXCR4/metabolism ; Signal Transduction/genetics ; Signal Transduction/physiology
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.
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1. College of Medicine (의과대학) > Dept. of Radiation Oncology (방사선종양학교실) > 1. Journal Papers
Yonsei Authors
Cho, Jae Ho(조재호) ORCID logo https://orcid.org/0000-0001-9966-5157
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