Glioblastoma multiforme (GBM) is the most devastating and common primary malignant brain tumor in adults. Angiogenesis as a hallmark in glioblastoma has attracted more and more attention of the research community. Over the past years, several systematic studies have provided vital results in this field discovering alterations in unanticipated number of genes and other regulatory factors and the associated signaling pathways. Recent discoveries about such genes and signaling pathway associated with angiogenesis in GBM provide a picture of the genomic routes in angiogenesis and antiangiogenesis pathways and may lay the foundation for improved antiangiogenesis therapy and clinical care. In this review, we discuss several such recent progresses in the genes associated with GBM angiogenesis/antiangiogenesis pathways and explore the potential new targets for GBM treatment.

Despite aggressive surgery, radiotherapy, and chemotherapy, malignant gliomas remain uniformly fatal. To progress, these tumors stimulate the formation of new blood vessels through processes driven primarily by angiogenesis factors. However, the resulting vessels are structurally and functionally abnormal and contribute to a hostile microenvironment that is highly selective for a more malignant phenotype with increased morbidity and mortality. Emerging preclinical and clinical data indicate that antiangiogenesis therapies are potentially effective regarding glioblastoma, and can transiently normalize tumor vessels. This creates a window of opportunity for optimally combining chemotherapeutics and radiation.

Background: Imaging features may be reflective of inherent disease biology and serve as potentially useful biomarkers in primary brain tumors. This study aimed to correlate conventional magnetic resonance imaging (MRI) features with O6-methylguanine-DNA-methyltransferase (MGMT) promoter methylation status and survival in glioblastoma. Methods: Conventional semantic imaging features were systematically extracted from preoperative MRI of 34 patients with glioblastoma by two reviewers independently and correlated with MGMT methylation status and survival using appropriate statistical tests. Results: MGMT promoter was methylated in 10 (30%) patients, unmethylated in 15 (44%) patients, and invalid or uninterpretable in 9 (26%) patients. Four imaging features, such as border, edema, contact with subventricular zone (SVZ), and necrosis, showed borderline correlation with methylation status. On multivariate logistic regression analysis, the odds of having methylated tumor were significantly reduced for tumors in contact with SVZ and borderline reduced for tumors with sharp borders. With a median follow-up of 18 months (interquartile range, 13–33 months), the median progression-free survival (PFS) and overall survival (OS) were 12.1 months (95% confidence interval [CI]: 9.9–14.3 months) and 17.1 months (95% CI: 12.6–21.5 months), respectively, for the study cohort. Among the semantic imaging features extracted from conventional MRI, only perilesional edema correlated significantly with PFS as well as OS. The hazards of both progression and death were significantly increased for tumors with moderate-to-severe edema on Cox regression analysis. Conclusion: Contact with SVZ and sharp tumor borders shows weak negative correlation with MGMT promoter methylation status in glioblastoma. Among all MRI features investigated in this work, moderate-to-severe edema is the only imaging feature that independently correlates with significantly inferior survival.

Background: Delta-like ligand 4 (DLL4) is a key Notch ligand implicated in tumor angiogenesis. However, previous studies have shown that the DLL4-Notch signaling inhibits tumor angiogenesis but promotes tumor progression in primary glioblastoma. The underlying mechanism remains unknown. Methods: Tumor tissues from 70 patients with primary glioblastoma were analyzed by immunohistochemistry for the expression of DLL4, microvessel density (MVD), and Ki67 labeling index. The degree of tumor contrast enhancement (DTCE) on preoperative magnetic resonance imaging was also evaluated. The effect on prognosis was assessed based on Kaplan–Meier survival and Cox proportional hazard models. Results: Results showed that the DTCE was negatively correlated with DLL4 but positively correlated with MVD (r = −0.260, 0.593, P < 0.05). The Ki67 labeling index was shown to be positively correlated with both DLL4 and MVD (r = 0.346, 0.346, P < 0.05). Univariate analysis indicated a significant correlation of high DLL4 and Ki67 labeling index expression with shorter progression-free survival (PFS) and overall survival (OS) (P < 0.05). Multivariate analysis confirmed high DLL4 and MVD expression as unfavorable prognostic indicators for PFS and OS (P < 0.05), and the hazard ratio of DLL4 was higher than MVD for both PFS and OS (P < 0.05). Conclusion: We conclude that the DLL4-Notch signaling improves tumor vascular function and contributes to the survival of malignant cells, resulting in less MVD but more tumor progression in primary glioblastoma.

Background: Glioma, notably glioblastoma multiforme, is characterized by extensive inter-and intra-tumoral heterogeneity. Surprisingly, the potential for differentiation of glioma cells has not been systematically analyzed and included in patient stratification methods. In the current study, retinoic acid (RA), a neuronal differentiation agent, was assessed for the pro-differentiative and anti-proliferative effects on glioma cells. Methods: Using RA-responsive glioma culture as an experimental paradigm, we analyzed the differentiation process both by videomicroscopy and at the mRNA (RNA-seq and reverse transcription-quantitative-polymerase chain reaction) and proteomic levels. Results: Glioma cells can differentiate into neurons in response to RA by (i) extending ultra-long cytoplasmic extensions, (ii) using these extensions to move from cell to cell either by perikaryal translocation or in a "spider-flight" like process, (iii) slowing their cell cycling, (iv) acquiring several neuronal differentiation markers such as MAPT, GAP43, DCX, NRCAM, NeuroD2, NeuroG2, and NeuN, and (v) decreasing the expression of several genes associated with glioma aggressiveness. Conclusion: These results indicate the existence of a subgroup of patients harboring RA-responsive glioma cells amenable to differentiation therapy, and stratifying such patients with a functional test is easily achievable. This provides the first step to reassess the potential of RA in the context of personalized medicine.