Hypoxia-inducible factor in cancer: from pathway regulation to therapeutic opportunity

Abstract

Cancer remains one of the most formidable challenges in modern medicine, due to its complex and dynamic nature, which demands innovative therapeutic approaches. One major challenge to cancer treatment is the tumour microenvironment and in particular tumour hypoxia (low oxygen levels), which contributes to tumour progression and immune evasion. At the cellular level, this is primarily governed by hypoxia-inducible factor (HIF). HIF is a transcription factor that orchestrates cellular responses to low oxygen levels, driving angiogenesis, metabolic adaptation and immune regulation. HIF’s dysregulation is frequently observed in various cancer types and correlates with increased aggressiveness, metastasis, resistance to therapy and poor patient prognosis. Consequently, understanding the cellular mechanisms underlying HIF activation and its downstream effects has become crucial to developing targeted cancer therapies for improving cancer patient outcomes and represents a key step towards precision medicine.Recent advancements in drug development have led to the emergence of HIF inhibitors, which aim to disrupt HIF-driven processes in cancer providing therapeutic benefit. Here, we provide a review of the molecular mechanisms through which HIF promotes tumour growth and resistance, emphasising the potential clinical benefits of HIF-targeted therapies. This review will discuss the challenges and opportunities associated with translating HIF inhibition into clinical practice, including ongoing clinical trials and future directions in the development of HIF-based cancer treatments.

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

“…The treatment of GBM has been challenging and often not radical, leading to recurrences and eventually shortened survival. The mechanisms behind treatment failure have been partly elucidated, with hypoxia playing the most crucial role by promoting both chemo- and radioresistance [ 6 , 90 , 91 ], as well as cell heterogeneity, resulting in various subpopulations [ 32 ]. We found eighteen studies investigated in 208 GBM, 15 cell lines or GBM-derived stem cell cultures, and 5 animal models, several therapeutic approaches concerning HIF-1α/VEGF ( Table 6 , Fig.…”

HIF-1 activated by PIM1 assembles a pathological transcription complex and regulon that drives JAK2V617F MPN disease

“…Of note, we observe that a significant proportion of differentially expressed VF_Hx signature genes were downregulated in MEPs. HIFs are not known to confer transcription-repressive functions [46,47], suggesting that peri-or posttranscriptional mechanisms mediated by HIF-1 and/or co-factors confer the observed transcript repression. In concert with these findings, cross analysis with ATACseq data showed no correlation between VF_Hx signature gene expression and accessibility and illustrated that very few of the VF_Hx signature genes showed increased site accessibility in JVF samples (Fig.…”

“…In both solid and haematological malignancies, HIFs are overexpressed as a result of two major factors: by hypoxic conditions - such as tumour or bone marrow microenvironments- and by genetic mutations, including those within VHL , p53 , Bcl2 , Myc , Ras and JAK (Malkov, Lee and Taylor, 2021). Whilst overexpression of the two predominant HIF isoforms (HIF-1, HIF-2) is widely observed, HIF-2 is demonstrated as almost exclusively oncogenic, whereas HIF-1 can confer either oncogenic or tumour suppressive functions (Keith, Johnson and Simon, 2011; Ortmann, 2024). This is particularly evident in myeloid neoplasia; in mouse models, inhibition of HIF-1 has been demonstrated as efficacious for treatment of myeloproliferative neoplasms (MPNs) (Baumeister et al ., 2020), whereas activation of HIF-1 was recently shown as efficacious for treatment of acute myeloid leukaemia (AML) (Lawson et al ., 2024).…”

Time, location and function of hypoxia-inducible factors are critical to therapeutic tumour response

“…The impact of hypoxia on cancer cell biology takes multiple forms, but the regulation of the hypoxia-inducible factor (HIF), sits at its core. The review written by Ortmann 3 provides an extensive overview of the regulation, function and therapeutic potential of these key dimeric protein complexes. The clarification that several isoforms of HIF exist, classified as 1, 2 or 3, and the fact that they operate in a chromatin environment that is also influenced by oxygenation immediately highlights the complexity in the molecular adaptation of cells, including cancer cells, to modifications in oxygen availability.…”

“…On reading Ortmann's review, 3 time, location and purpose emerge as three critical criteria to the relevance of HIF to the hypoxic and therapeutic tumour response. Time is relevant, for instance, to the stabilisation of HIF isoforms, each associated with their own kinetics.…”