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

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.

Cellular Plasticity in Cancer

“…42 and 43 ). In tumors, EndoMT has been found to be a source of cancer-associated fibroblasts ( 44 ) and was recently shown to promote lung fibrosis and tumorigenesis ( 45 ), as well as protumorigenic macro phage polarization ( 46 ).…”

TGF-β-Induced Endothelial to Mesenchymal Transition in Disease and Tissue Engineering

“…EndMT is also related to radiation therapy. Choi et al (2018) showed that radiation could induce EndMT, which triggered tumor-associated macrophage (TAM) polarization toward an M2 phenotype and resulted in radiation resistance. Additionally, CAFs can support immune evasion and act as an immunosuppressive agent in cancer immunotherapy, by inducing the secretion of multiple chemokines and cytokines, such as TGF-β and IL-6/8/13, and thereby inhibit the antitumor immune response.…”

Effect of X-rays on transcript expression of rat brain microvascular endothelial cells: role of calcium signaling in X-ray-induced endothelium damage

“…Tight junctions consist primarily of intrinsic transmembrane proteins, scaffold proteins, and regulatory molecules between cells [10]. Studies have shown that tight junctions between vascular endothelial cells play a critical role in the BBB [11]. Thus, most studies on the effects of radiation on blood vessels have focused on endothelial cells [7].…”

“…High-throughput technology enables comprehensive monitoring of biological systems and provides an entry point to clarify molecular mechanisms that are involved in cell responses to environment changes. Therefore, we investigated the effect of a dose of X-rays (20 Gy) on transcripts in rat BMECs [11,12] to provide a theoretical basis for understanding the molecular mechanisms underpinning radiotherapy-induced brain edema. The results of the present study may also offer potential targets for future drug development.…”