Abstract
Rather than targeting tumour cells directly, elements of the tumour microenvironment can be modulated to sensitize tumours to the effects of therapy. Here we report a unique mechanism by which ectopic microRNA-103 can manipulate tumour-associated endothelial cells to enhance tumour cell death. Using gain-and-loss of function approaches, we show that miR-103 exacerbates DNA damage and inhibits angiogenesis in vitro and in vivo. Local, systemic or vascular-targeted delivery of miR-103 in tumour-bearing mice decreased angiogenesis and tumour growth. Mechanistically, miR-103 regulation of its target gene TREX1 in endothelial cells governs the secretion of pro-inflammatory cytokines into the tumour microenvironment. Our data suggest that this inflammatory milieu may potentiate tumour cell death by supporting immune activation and inducing tumour expression of Fas and TRAIL receptors. Our findings reveal miR-mediated crosstalk between vasculature and tumour cells that can be exploited to improve the efficacy of chemotherapy and radiation.
Highlights
Rather than targeting tumour cells directly, elements of the tumour microenvironment can be modulated to sensitize tumours to the effects of therapy
We observed that silencing of the microRNA processing enzyme Dicer in human umbilical vein endothelial cells (ECs) significantly increased DNA damage in these cells as measured by a Comet assay (Supplementary Fig. 1)
To identify specific miR(s) involved in this function, we screened for miRs that were differentially expressed in ECs 6 h after irradiation or treatment with cisplatin or hydrogen peroxide (Supplementary Fig. 2) and found miR-103 as the top candidate among a set of seven miRs upregulated in response to all three inducers of intrinsic apoptosis (Fig. 1a,b)
Summary
DDR induces miR-103 and miR-103 exacerbates DNA damage. We observed that silencing of the microRNA processing enzyme Dicer in human umbilical vein ECs significantly increased DNA damage in these cells as measured by a Comet assay (Supplementary Fig. 1). Treatment of subcutaneous HCT-116 colon carcinoma xenografts with three doses of a miR-103 mimic and a single dose of radiation significantly decreased tumour burden (Fig. 3b) when compared with mice that received a control mimic. Consistent with our in vitro observations on angiogenic sprouting, there was a 60% decrease in vascular area (CD31 staining) in mice that received both miR-103 and radiation (Fig. 3c) a week after the last miR-103 injection. To address whether this effect was due to the action of miR-103 on the tumour endothelium, we utilized a recently characterized[11,12] EC targeted nanoparticle 7C1 to deliver miR-103. Bars show CD31 area normalized the tumour area as mean þ s.e.m. from n 1⁄4 4 tumours per group. *Po0.05 by two-tailed Student’s t-test
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