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Glioblastoma-derived tumor cells induce vasculogenic mimicry through Flk-1 protein activation.

ABSTRACT: Glioblastoma (GBM) is extremely aggressive and essentially incurable. Its malignancy is characterized by vigorous microvascular proliferations. Recent evidence has shown that tumor cells display the ability to drive blood-perfused vasculogenic mimicry (VM), an alternative microvascular circulation independent of endothelial cell angiogenesis. However, molecular mechanisms underlying this vascular pathogenesis are poorly understood. Here, we found that vascular channels of VM in GBM were composed of mural-like tumor cells that strongly express VEGF receptor 2 (Flk-1). To explore a potential role of Flk-1 in the vasculogenesis, we investigated two glioblastoma cell lines U87 and GSDC, both of which express Flk-1 and exhibit a vascular phenotype on Matrigel. Treatment of both cell lines with either Flk-1 gene knockdown or Flk-1 kinase inhibitor SU1498 abrogated Flk-1 activity and impaired vascular function. Furthermore, inhibition of Flk-1 activity suppressed intracellular signaling cascades, including focal adhesion kinase and mitogen-activated protein kinase ERK1/2. In contrast, blockade of VEGF activity by the neutralizing antibody Bevacizumab failed to recapitulate the impact of SU1498, suggesting that Flk-1-mediated VM is independent of VEGF. Xenotransplantation of SCID/Beige mice with U87 cells and GSDCs gave rise to tumors harboring robust mural cell-associated vascular channels. Flk-1 shRNA restrained VM in tumors and subsequently inhibited tumor development. Collectively, all the data demonstrate a central role of Flk-1 in the formation of VM in GBM. This study has shed light on molecular mechanisms mediating tumor aggressiveness and also provided a therapeutic target for patient treatment.

SUBMITTER: Francescone R

PROVIDER: S-EPMC3397909 | biostudies-other | 2012 Jul

REPOSITORIES: biostudies-other

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Glioblastoma-derived tumor cells induce vasculogenic mimicry through Flk-1 protein activation.

Francescone Ralph R Scully Steve S Bentley Brooke B Yan Wei W Taylor Sherry L SL Oh Dennis D Moral Luis L Shao Rong R

The Journal of biological chemistry 20120531 29

Glioblastoma (GBM) is extremely aggressive and essentially incurable. Its malignancy is characterized by vigorous microvascular proliferations. Recent evidence has shown that tumor cells display the ability to drive blood-perfused vasculogenic mimicry (VM), an alternative microvascular circulation independent of endothelial cell angiogenesis. However, molecular mechanisms underlying this vascular pathogenesis are poorly understood. Here, we found that vascular channels of VM in GBM were composed ...[more]

PMID: 22654102

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Project description:Vasculogenic mimicry (VM) has been identified as an important vasculogenic mechanism in malignant tumors, but little is known about its clinical meanings and mechanisms in oligodendroglioma. In this study, VM-positive cases were detected in 28 (20.6%) out of 136 oligodendroglioma samples, significantly associated with higher WHO grade, lower Karnofsky performance status (KPS) scores, and recurrent tumor (p < 0.001, p = 0.040, and p = 0.020 respectively). Patients with VM-positive oligodendroglioma had a shorter progress-free survival (PFS) compared with those with VM-negative tumor (p < 0.001), whereas no significant difference was detected in overall survival (OS) between these patients. High levels of phosphorylate serine/threonine kinases Ataxia-telangiectasia mutated (pATM) and phosphorylate Ataxia-telangiectasia and Rad3-Related (pATR) were detected in 31 (22.8%) and 34 (25.0%), respectively out of 136 oligodendroglioma samples. Higher expressions of pATM and pATR were both associated with a shorter PFS (p < 0.001 and p < 0.001). VM-positive oligodendroglioma specimens tended to exhibit higher pATM and pATR staining than VM-negative specimens (rs = 0.435, p < 0.001 and rs = 0.317, p < 0.001). Besides, Hypoxia-inducible factor-1α (HIF1α) expression was detected in 14(10.3%) samples, correlated with higher WHO grade and non-frontal lobe (p = 0.010 and p = 0.029). However, no obvious connection was detected between HIF1α expression and VM formation (p = 0.537). Finally, either univariate or multivariate analysis suggested that VM was an independent unfavorable predictor for oligodendroglioma patients (p < 0.001, HR = 7.928, 95%CI: 3.382-18.584, and p = 0.007, HR = 4.534, 95%CI: 1.504-13.675, respectively). VM is a potential prognosticator for tumor progression in oligodendroglioma patients. Phosphorylation of ATM and ATR linked to treatment-resistance may be associated with VM formation. The role of VM in tumor progression and the implication of pATM/pATR in VM formation may provide potential therapeutic targets for oligodendroglioma treatment.

Project description:BackgroundGlioblastoma, the most common primary malignant brain tumour in adults, is a highly vascular tumour characterised by abnormal angiogenesis. Additional mechanisms of tumour vascularisation have also been reported in glioblastoma, including the formation of tumour cell-derived vessels by vasculogenic mimicry (VM) or the transdifferentiation of tumour cells to endothelial cells. VM and endothelial transdifferentiation have frequently been reported as distinct processes, however, the use of both terms to describe a single process of vascularisation also occurs. Some overlapping characteristics have also been reported when identifying each process. We therefore aimed to determine the markers consistently attributed to VM and endothelial transdifferentiation in the glioblastoma literature.MethodsOvid MEDLINE and Ovid Embase were searched for studies published between January 1999 and July 2021 that assessed VM or tumour to endothelial transdifferentiation in human glioblastoma. The online systematic review tool Covidence was used for screening and data extraction. Extracted data included type of tumour-derived vasculature reported, methods and techniques used, and markers investigated. Studies were grouped based on type of vasculature reported for further assessment.ResultsOne hundred and thirteen of the 419 unique records identified were included for analysis. VM was reported in 64/113 studies, while tumour to endothelial transdifferentiation was reported in 16/113 studies. The remaining studies used both terms to describe a single process, did not define the process that occurred, or concluded that neither VM nor endothelial transdifferentiation occurred. Absence of CD34 and/or CD31 in vascular structures was the most common indicator of VM, while expression of CD34 and/or CD31, in addition to various other endothelial, stem cell or tumour cell markers, indicated tumour to endothelial transdifferentiation.ConclusionCells derived from tumour to endothelial transdifferentiation express typical endothelial markers including CD34 and CD31, while tumour cells contributing to VM lack CD34 and CD31 expression. Additional tumour markers are required to identify transdifferentiation in glioblastoma tissue, and this process requires further characterisation.

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Glioblastoma-derived tumor cells induce vasculogenic mimicry through Flk-1 protein activation.

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Glioblastoma-derived tumor cells induce vasculogenic mimicry through Flk-1 protein activation.

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