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.
Highlights
It remains controversial whether targeting tumour vasculature can improve radiotherapeutic efficacy
At 48 h post irradiation, Trp[53] silencing in human umbilical vein ECs (HUVECs) markedly inhibited irradiation-induced messenger RNA expression of Snail[1], Snail[2], and Zeb[2], which encode transcription factors implicated in EndMT29, compared to control small interfering RNA (siRNA)-treated cells, whereas Tgfbr[2] knockdown increased their expression (Supplementary Fig. 1a, b)
Because blood monocytes secrete SDF-1, which promotes their differentiation into macrophages[36], we investigated the effects of monocytic SDF-1 recruitment and endothelial CXCR4 on radiotherapy outcome
Summary
It remains controversial whether targeting tumour vasculature can improve radiotherapeutic efficacy. Trp[53] (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. CXCR4 upregulation in radioresistant tumour ECs was highly associated with SDF-1+ TAM recruitment and M2 polarization of TAMs, which was suppressed by Trp[53] deletion These EndMT-related phenomena were observed in irradiated human lung cancer tissues. Our findings suggest that targeting tumour EndMT might enhance radiotherapy efficacy by inhibiting the reactivation of dormant hypoxic CSCs and promoting anti-tumour immune responses. Tumour-vasculature development after radiotherapy is not well characterized, targeting tumour ECs enhances radiotherapeutic efficacy; ceramide, sphingomyelinase, and Bax regulate EC apoptosis after irradiation[9,10]. ECs lacking ataxia-telangiectasia mutated showed increased radiosensitivity[13] It remains debatable whether EC targeting can improve radiotherapy efficacy. Radioimmunomodulation studies have revealed crucial strategies for effectively combining immunotherapy and radiotherapy
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