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Review
. 2024 May 30;16(11):2089.
doi: 10.3390/cancers16112089.

Understanding the Significance of Hypoxia-Inducible Factors (HIFs) in Glioblastoma: A Systematic Review

Emir Begagić  1 , Hakija Bečulić  2   3 , Amina Džidić-Krivić  4 , Samra Kadić Vukas  4 , Semir Hadžić  5 , Alma Mekić-Abazović  6 , Sabina Šegalo  7 , Emsel Papić  7 , Emmanuel Muchai Echengi  8 , Ragib Pugonja  3 , Tarik Kasapović  5 , Dalila Kavgić  5 , Adem Nuhović  9 , Fatima Juković-Bihorac  10   11 , Slaviša Đuričić  11 , Mirza Pojskić  12
Affiliations
Review

Understanding the Significance of Hypoxia-Inducible Factors (HIFs) in Glioblastoma: A Systematic Review

Emir Begagić et al. Cancers (Basel). .

Abstract

Background: The study aims to investigate the role of hypoxia-inducible factors (HIFs) in the development, progression, and therapeutic potential of glioblastomas.

Methodology: The study, following PRISMA guidelines, systematically examined hypoxia and HIFs in glioblastoma using MEDLINE (PubMed), Web of Science, and Scopus. A total of 104 relevant studies underwent data extraction.

Results: Among the 104 studies, global contributions were diverse, with China leading at 23.1%. The most productive year was 2019, accounting for 11.5%. Hypoxia-inducible factor 1 alpha (HIF1α) was frequently studied, followed by hypoxia-inducible factor 2 alpha (HIF2α), osteopontin, and cavolin-1. Commonly associated factors and pathways include glucose transporter 1 (GLUT1) and glucose transporter 3 (GLUT3) receptors, vascular endothelial growth factor (VEGF), phosphoinositide 3-kinase (PI3K)-Akt-mechanistic target of rapamycin (mTOR) pathway, and reactive oxygen species (ROS). HIF expression correlates with various glioblastoma hallmarks, including progression, survival, neovascularization, glucose metabolism, migration, and invasion.

Conclusion: Overcoming challenges such as treatment resistance and the absence of biomarkers is critical for the effective integration of HIF-related therapies into the treatment of glioblastoma with the aim of optimizing patient outcomes.

Keywords: brain neoplasms; glial tumors; hypoxia; microenvironment; targeted therapy.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
PRISMA flow diagram.
Figure 2
Figure 2
Geographical distribution of included studies.
Figure 3
Figure 3
Temporal distribution of included studies.
Figure 4
Figure 4
Study design of included studies.
Figure 5
Figure 5
Commonly investigated signaling pathways involving hypoxia-inducible factors (HIFs) in glioblastoma. Vascular endothelial growth factor (VEGF) and growth factors (GFs) activate Receptor Tyrosine Kinases (RTKs), triggering downstream signaling. The PI3K (Phosphoinositide 3-Kinase) pathway, inhibited by PTEN (Phosphatase and Tensin Homolog), activates Akt, leading to enhanced cell survival via the Bcl2 inhibition of apoptosis and mTOR (mechanistic target of rapamycin) promotion of growth. The RAS/MAPK (Mitogen-Activated Protein Kinase) pathway, through Raf, MEK, and ERK, also supports cell proliferation and survival. HIF-1α (hypoxia-inducible factor 1-alpha) under hypoxia increases glycolysis for energy production and gene expression for adaptation, regulated by HIF-1β (hypoxia-inducible factor 1-beta). HIF-1α stability is controlled by ubiquitination via MDM2 (Mouse Double Minute 2) and proteasomal degradation influenced by p53. Reactive oxygen species (ROS) and Calcium ion (Ca2+) signaling activate survival pathways, involving LKB1 (Liver Kinase B1), AMPK (AMP-activated Protein Kinase), and CaMK2 (Calcium/Calmodulin-Dependent Protein Kinase II). Glucose transporters Glut1/3 facilitate glucose uptake. This network highlights potential therapeutic targets, such as mTOR, PI3K, and HIF-1α, to disrupt glioblastoma cell survival and adaptation mechanisms. The figure was created using the BioRender online commercial platform.
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