Abstract
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.
Highlights
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
We investigated the impact of VM formation on prognosis in oligodendroglioma patients with different tumor grades as well as in primary and recurrent oligodendrogliomas
These results suggest that VM formation may affect the progression of oligodendroglioma but not the overall tumor growth, resulting in a shorter progress-free survival (PFS) but no impact on overall survival (OS)
Summary
Evaluated as prognostic indexes [23,24,25,26]. Both ATM and ATR play important roles in pathological angiogenesis [27,28], but little is known about the involvement of ATM/ATR in VM formation. Active vascular formation characterized by dense network of blood vessels in oligodendrogliomas indicates a potential relationship between angiogenesis and tumor progression. VM formation shows a significant influence on tumor differentiation, invasion, and metastasis, so it presents as an unfavorable prognostic indicator in cancer patients [11, 12] This alternative mechanism of angiogenesis utilized by tumor cells may be VEGF-independent and could escape from antiangiogenic therapy targeting VEGF, which partially explains the disappointing results of traditional angiogenesis inhibitors [13,14,15]. Serine/threonine kinases Ataxia-telangiectasia mutated (ATM) and Ataxia-telangiectasia and Rad3-Related (ATR) are well known as major regulators in DNA damage response (DDR), both belonging to the phosphatidylinositol 3-kinase (PI3K)related protein kinase (PIKK) family They have cross-talks and take effect synergistically to activate downstream pathways [17].
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