Review | 1 February 2024
Hypoxia-inducible factor in cancer: from pathway regulation to therapeutic opportunityBrian M Ortmann
Multiple lines of evidence confirm the strong association between the presence of hypoxia in solid tumours and poorer outcomes in patients with cancer resulting from both more aggressive tumour cell behaviour and impaired responses to therapy.1 2 With well over 12 000 articles published in the past 5 years alone (source, PubMed), the importance of hypoxia in cancer is indisputable. 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 Ortmann3 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.4 The isoforms influence distinct downstream genes that inform longer-term adaptation to reduced oxygen levels. These include the development of the tumour vasculature, although this is accepted to be disorganised and dysfunctional, leading to variable and varying, oxygenation levels. This apparent flaw in the capacity of tumours to sustain their development through adequate blood supply may actually provide cancer cells with a powerful tool against therapeutic injury. Antiangiogenic therapies, originally proposed to starve the tumour of oxygen and nutrients, paradoxically are proving useful in improving tumour oxygenation levels, which in turn can make the tumour more susceptible to treatments.5
Location is relevant because isoform activity is cell-type specific and has tissue-specific consequences.6 The evolutionary pressures that have shaped the ‘purpose’ of the HIF system relate to the reproductive period of life and are little influenced by tumour biology that most commonly occurs in the postreproductive period. HIF activation entrains a fixed gene regulatory system that spans modifications in metabolism, angiogenesis and cells invasion and migration. More than a simple switch, HIF isoform amounts are normally sequenced and balanced to induce the required cellular response. Importantly, in the context of malignancy HIF activation has both protumourigenic and antitumourigenic effects.7 These may be cell autonomous or systemic and depend both on the amount and balance of HIF isoform activation. A further complexity is the relationship between hypoxia, HIFs and the development of metastases which is often the central determinant of patient outcome.8 How these features contribute to differential therapeutic outcomes across cancer types, or the risk of toxicity associated with the therapeutic targeting of this system is the subject of ongoing study.
Ortmann’s review also highlights that HIF stabilisation can occur in well-oxygenated cells, in response to the metabolic environment of the cell. This phenomenon, which also occurs in von Hippel–Lindau (VHL) disease/pheochromocytoma and/or paraganglioma (PPGL) and can result from iron chelation, has been referred to as ‘pseudo hypoxia’.8 ,9 The similarities and differences between HIF-mediated molecular responses in hypoxic and oxygenated environments and their potential clinical relevance warrants further discussion.
In conclusion, there are clear relationships between the HIF system, cancer and its treatments, but areas of uncertainty, where further research is required, remain. The options for the therapeutic targeting of HIF now exist, and will, no doubt, lead to novel clinical trials in the coming years.
