The glioblastoma vasculature as a target for cancer therapy

Dimberg, Anna

doi:10.1042/bst20140278

Cited by 44 publications

(52 citation statements)

References 63 publications

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“…Since anti-angiogenic agents have been successful in the treatment of glioblastomas and colorectal carcinomas8910, we chose to investigate the effects of miR-103 in mouse xenograft models of these two tumour types. Strikingly, local delivery of miR-103 a week after tumour implantation increased survival in an aggressive orthotopic glioblastoma model (Fig.…”

Section: Resultsmentioning

confidence: 99%

MicroRNA regulation of endothelial TREX1 reprograms the tumour microenvironment

et al. 2016

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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.

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Section: Resultsmentioning

confidence: 99%

MicroRNA regulation of endothelial TREX1 reprograms the tumour microenvironment

et al. 2016

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“…In practice, GBM vessels are highly dysfunctional, which makes penetration of the GBM by nutrients difficult, leading to formation of a nutrient-poor and hypoxic core [21]. Vessel dysfunction could also restrict the effect of crosstalk at the tumor core.…”

Section: Discussionmentioning

confidence: 99%

Multiscale Modeling of Glioblastoma Suggests that the Partial Disruption of Vessel/Cancer Stem Cell Crosstalk Can Promote Tumor Regression without Increasing Invasiveness

Yan

Romero-López

Frieboes

et al. 2016

IEEE Trans. Biomed. Eng.

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Objective In glioblastoma, the crosstalk between vascular endothelial cells (VECs) and glioma stem cells (GSCs) has been shown to enhance tumor growth. We propose a multiscale mathematical model to study this mechanism, explore tumor growth under various initial and microenvironmental conditions and investigate the effects of blocking this crosstalk. Methods We develop a hybrid continuum-discrete model of highly organized, vascularized tumors. VEC-GSC crosstalk is modeled via VEGF production by tumor cells and by secretion of soluble factors by VECs that promote GSC self-renewal and proliferation. Results VEC-GSC crosstalk increases both tumor size and GSC fraction by enhancing GSC activity and neovascular development. VEGF promotes vessel formation, and larger VEGF sources typically increase vessel numbers, which enhances tumor growth and stabilizes the tumor shape. Increasing the initial GSC fraction has a similar effect. Partially disrupting the crosstalk by blocking VEC secretion of GSC promoters reduces tumor size but does not increase invasiveness, which is in contrast to anti-angiogenic therapies, which reduce tumor size but may significantly increase tumor invasiveness. Significance Multiscale modeling supports the targeting of VEC-GSC crosstalk as a promising approach for cancer therapy.

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“…38 The most important components of tumor vascularity, endothelial cells, are the main target through which glioma regulates angiogenesis by secretion of multiple pro-angiogenic growth factors such as VEGF, transforming growth factor-β (TGFβ), platelet-derived growth factor-B (PDGF-B), and pleiotrophin. 1 Recent research showed that the glioma microenvironment also triggered a change in vascular endothelial cell gene expression; whether this change takes part in glioma angiogenesis remains controversial. 39,40 There is increasing evidence that lncRNAs not only affect the biological behaviors of tumor cells directly but also regulate the function of tumor vascular endothelial cells.…”

Section: Discussionmentioning

confidence: 99%

“…Even after standard treatment, the prognosis of glioblastoma remains poor, with an average survival time of only 12-15 months. 1 The failure of traditional radiotherapy and chemotherapy to improve patient survival past this window has led to increased attention paid to developing therapies directed at molecular targets. [2][3][4] As a prototypical angiogenesisdependent solid tumor, glioma characteristically promotes the growth of tumor blood vessels, which is one of the main reasons for the failure of conventional therapy.…”

Section: Introductionmentioning

confidence: 99%

PVT1 affects growth of glioma microvascular endothelial cells by negatively regulating miR-186

Wang

Xue

et al. 2017

Tumour Biol.

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Vigorous angiogenesis is one of the reasons for the poor prognosis of glioma. A number of studies have shown that long non-coding RNA can affect a variety of biological behaviors of tumors. However, the influence of long non-coding RNAs on glioma vascular endothelial cells remains unclear. To simulate the glioma microenvironment, we applied glioma-conditioned medium to human cerebral microvascular endothelial cells. The long non-coding RNA PVT1 was found to be highly expressed in glioma vascular endothelial cells. Cell Counting Kit-8, migration, and tube formation assays showed that PVT1 overexpression promoted glioma vascular endothelial cells proliferation, migration, and angiogenesis. We also found that PVT1 overexpression upregulated the expression of the autophagy-related proteins Atg7 and Beclin1, which induced protective autophagy. Bioinformatics software and dual-luciferase system analysis confirmed that PVT1 acts by targeting miR-186. In addition, our study showed that miR-186 could target the 3′ untranslated region of Atg7 and Beclin1 to decrease their expression levels, thereby inhibiting glioma-conditioned human cerebral microvascular endothelial cell autophagy. In conclusion, PVT1 overexpression increased the expression of Atg7 and Beclin1 by targeting miR-186, which induced protective autophagy, thus promoting glioma vascular endothelial cell proliferation, migration, and angiogenesis. Therefore, PVT1 and miR-186 can provide new therapeutic targets for future anti-angiogenic treatment of glioma.

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The glioblastoma vasculature as a target for cancer therapy

Cited by 44 publications

References 63 publications

MicroRNA regulation of endothelial TREX1 reprograms the tumour microenvironment

MicroRNA regulation of endothelial TREX1 reprograms the tumour microenvironment

Multiscale Modeling of Glioblastoma Suggests that the Partial Disruption of Vessel/Cancer Stem Cell Crosstalk Can Promote Tumor Regression without Increasing Invasiveness

PVT1 affects growth of glioma microvascular endothelial cells by negatively regulating miR-186

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