Open Access

REVIEW

Hypoxia-inducible factor 1alpha and vascular endothelial growth factor in Glioblastoma Multiforme: a systematic review going beyond pathologic implications

DIMITRA P. VAGELI^1,2,*, PANAGIOTIS G. DOUKAS³, KERASIA GOUPOU², ANTONIOS D. BENOS², KYRIAKI ASTARA^2,4, KONSTANTINA ZACHAROULI², SOTIRIS SOTIRIOU⁵, MARIA IOANNOU²

1 Department of Surgery, Yale University, New Haven, CT 06510, USA
2 Department of Pathology, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa, 41500, Greece
3 Department of Medicine, Rutgers/Saint Peter’s University Hospital, New Brunswick, NJ 08901, USA
4 Department of Neurology, Army Share Fund Hospital (NIMTS), Athens, 11521, Greece
5 Laboratory of Embryology, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa, 41500, Greece

* Corresponding Authors: DIMITRA P. VAGELI. Email: ,

Oncology Research 2024, 32(8), 1239-1256. https://doi.org/10.32604/or.2024.052130

Received 24 March 2024; Accepted 23 May 2024; Issue published 17 July 2024

Abstract

Glioblastoma multiforme (GBM) is an aggressive primary brain tumor characterized by extensive heterogeneity and vascular proliferation. Hypoxic conditions in the tissue microenvironment are considered a pivotal player leading tumor progression. Specifically, hypoxia is known to activate inducible factors, such as hypoxia-inducible factor 1alpha (HIF-1α), which in turn can stimulate tumor neo-angiogenesis through activation of various downward mediators, such as the vascular endothelial growth factor (VEGF). Here, we aimed to explore the role of HIF-1α/VEGF immunophenotypes alone and in combination with other prognostic markers or clinical and image analysis data, as potential biomarkers of GBM prognosis and treatment efficacy. We performed a systematic review (Medline/Embase, and Pubmed database search was completed by 16th of April 2024 by two independent teams; PRISMA 2020). We evaluated methods of immunoassays, cell viability, or animal or patient survival methods of the retrieved studies to assess unbiased data. We used inclusion criteria, such as the evaluation of GBM prognosis based on HIF-1α/VEGF expression, other biomarkers or clinical and imaging manifestations in GBM related to HIF-1α/VEGF expression, application of immunoassays for protein expression, and evaluation of the effectiveness of GBM therapeutic strategies based on HIF-1α/VEGF expression. We used exclusion criteria, such as data not reporting both HIF-1α and VEGF or prognosis. We included 50 studies investigating in total 1319 GBM human specimens, 18 different cell lines or GBM-derived stem cells, and 6 different animal models, to identify the association of HIF-1α/VEGF immunophenotypes, and with other prognostic factors, clinical and macroscopic data in GBM prognosis and therapeutic approaches. We found that increased HIF-1α/VEGF expression in GBM correlates with oncogenic factors, such as miR-210-3p, Oct4, AKT, COX-2, PDGF-C, PLDO3, M2 polarization, or ALK, leading to unfavorable survival. Reduced HIF-1α/VEGF expression correlates with FIH-1, ADNP, or STAT1 upregulation, as well as with clinical manifestations, like epileptogenicity, and a favorable prognosis of GBM. Based on our data, HIF-1α or VEGF immunophenotypes may be a useful tool to clarify MRI-PET imaging data distinguishing between GBM tumor progression and pseudoprogression. Finally, HIF-1α/VEGF immunophenotypes can reflect GBM treatment efficacy, including combined first-line treatment with histone deacetylase inhibitors, thimerosal, or an active metabolite of irinotecan, as well as STAT3 inhibitors alone, and resulting in a favorable tumor prognosis and patient survival. These data were supported by a combination of variable methods used to evaluate HIF-1α/VEGF immunophenotypes. Data limitations may include the use of less sensitive detection methods in some cases. Overall, our data support HIF-1α/VEGF’s role as biomarkers of GBM prognosis and treatment efficacy.

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