How hypoxia-inducible factors drive angiogenesis in glioblastoma
Glioblastoma (GBM) is one of the most aggressive forms of brain cancer. Despite advances in surgery, radiation, and chemotherapy, the prognosis remains poor, with median survival typically under 15 months1. One of the reasons GBM is so difficult to treat is its ability to rapidly form new blood vessels, a process known as angiogenesis. This vascular growth supports tumor expansion and contributes to treatment resistance2. These features are not unique to GBM; hypoxic microenvironments surrounding cancerous tumors in general promote angiogenesis and cancer growth, making malignant brain tumors particularly challenging to manage.
But what drives this intense angiogenic activity? Research is increasingly pointing to hypoxia-inducible factors (HIFs) as key regulators of this process. These transcription factors help cells adapt to low oxygen levels, a common feature of the GBM microenvironment. Understanding how HIFs influence angiogenesis could open new avenues for therapeutic intervention3-4.
What are hypoxia-inducible factors (HIFs)?
Hypoxia-inducible factors are proteins that regulate gene expression in response to oxygen availability. The two most studied isoforms are HIF-1α and HIF-2α. Under normal oxygen conditions (normoxia), these proteins are rapidly degraded. However, in low oxygen environments (hypoxia), they stabilize and translocate to the nucleus, where they activate a range of genes involved in survival, metabolism, and vascular development5.
Among their downstream targets are vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and glucose transporter 1 (GLUT1). These molecules play important roles in promoting blood vessel formation, cell proliferation, and metabolic adaptation. In the context of GBM, this means that HIFs help the tumor survive and grow in an otherwise hostile environment6.
Hypoxia in the glioblastoma microenvironment
GBM tumors are known for their chaotic and poorly organized vasculature. As the tumor grows, parts of it become deprived of oxygen due to an insufficient blood supply. This leads to regions of hypoxia, which in turn activate HIF signaling. Hypoxia and HIF-1 can modulate inflammatory responses and influence cancer cell behavior, promoting tumor progression and adaptation within the microenvironment7.
One hallmark of GBM histology is pseudopalisading necrosis, where tumor cells surround areas of dead tissue. These regions are typically hypoxic and are associated with increased HIF activity8. Hypoxia not only promotes angiogenesis but also contributes to therapy resistance by altering cell metabolism and reducing the effectiveness of radiation and chemotherapy. Hypoxia and HIF activity contribute to the survival of cancer cells and may be considered risk factors for poor prognosis.
HIF-mediated angiogenesis and vascular endothelial growth factor in GBM
Once stabilized, HIFs initiate a cascade of events that promote angiogenesis. One of the most well-known targets is VEGF, a protein that stimulates the growth of new blood vessels. In GBM, VEGF expression is often elevated, leading to the formation of abnormal, leaky vasculature that supports tumor growth but also contributes to edema and poor drug delivery9.
This creates a feedback loop: hypoxia leads to HIF activation, which increases VEGF and other pro-angiogenic factors, such as angiopoietin-2 (ANGPT2), fibroblast growth factor (FGF), and stromal cell-derived factor 1 (SDF-1), resulting in new but inefficient blood vessels. Stalk cells proliferate behind tip cells during sprouting angiogenesis, but the resulting vessels often fail to maintain adequate blood flow to metabolically active tissue. These vessels fail to adequately oxygenate the tumor, perpetuating the hypoxic environment and further driving HIF activity.
Research highlights and emerging insights
Recent studies have begun to differentiate the roles of HIF-1α and HIF-2α in GBM. While both contribute to angiogenesis, HIF-2α has been implicated in maintaining glioma stem-like cells and may play a more prominent role in tumor progression10. This has led to interest in developing selective HIF-2α inhibitors as potential therapies.
Advanced models, such as patient-derived xenografts and 3D organoids, are helping researchers study HIF signaling in more physiologically relevant settings. These models allow a better understanding of how hypoxia and angiogenesis interact in the complex tumor microenvironment11.
Scientists are also exploring how HIFs work with other key pathways like Notch and PI3K/AKT. These pathways play crucial roles in blood vessel formation and tumor survival. This research opens doors to smarter, more precise treatment approaches12.
Therapeutic implications
Scientists have been targeting blood vessel growth in GBM therapy for over ten years now. For example, bevacizumab blocks VEGF and shows real promise in reducing brain swelling and slowing disease progression13. But here's the challenge – it hasn't dramatically improved how long patients live. Why? Tumors are clever. They adapt by switching on backup blood vessel pathways or becoming more invasive.
This pushes us toward targeting HIFs directly. Researchers are developing small-molecule drugs that block HIF-2α activity. Small-molecule inhibitors and HIF inhibitors are being evaluated in phase III clinical trials for various human cancers and other diseases14. Some are already in clinical trials for different cancers. These compounds work by disrupting how HIFs control gene activity, which could cut off blood supply to tumors and slow their growth. Topoisomerase I-mediated inhibition is also being explored to reduce HIF-1 activity. Angiogenesis inhibitors and small-molecule inhibitor therapies are also being tested for cancer treatment, myocardial infarction, myocardial ischemia-reperfusion injury, pulmonary fibrosis, and acute respiratory distress syndrome15.
Combination treatments also show real promise. Picture pairing HIF blockers with immune checkpoint inhibitors or drugs targeting tumor metabolism could significantly boost treatment success. We're also moving toward personalized approaches. By using biomarkers that detect oxygen levels or HIF activity, we can identify which patients will benefit most from these targeted strategies16.
Future directions
Despite progress, many questions remain. Can we selectively inhibit HIFs in tumor cells without affecting normal tissue? What biomarkers can reliably predict response to HIF-targeted therapies? How do HIFs interact with the immune system and other components of the tumor microenvironment?
Emerging technologies such as multi-omics profiling and artificial intelligence are helping to unravel these complex networks. By integrating data from genomics, transcriptomics, proteomics, and imaging, researchers can build more comprehensive models of HIF signaling and its role in GBM.
As our understanding deepens, there is hope that targeting hypoxia and angiogenesis will become a more effective part of the GBM treatment landscape. For now, HIFs remain a promising but challenging target in the fight against this aggressive cancer.
References
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