The Nobel Prize in Physiology or Medicine for 2019 was jointly awarded to three scientists, William G. Kaelin Jr, Sir Peter J. Ratcliffe and Gregg L. Semenza, for their pioneering work on how cells sense and adapt to oxygen deficiency (Hypoxia). Hypoxia (partial pressure of oxygen<10mm Hg) exists in various physiological and pathological conditions. Hypoxic regions are commonly observed in solid tumors, resulting from rapid growth of cancer cells and abnormal vasculature, leading to oxygen and nutrient deprivation. Areas of acute (cycling with intermittent hypoxia) or chronic hypoxia (for days) are observed depending upon the local vasculature. The tumour microenvironment thus has subpopulations of cancer cells with gradients of O2 content, pH, metabolism, genomic stability and aggressiveness.
When cancer cells sense hypoxia, they undergo various adaptive changes, which allow them to sustain and proliferate in these conditions. Hypoxic effects are mainly mediated by two key oxygen labile transcription factors, called Hypoxia-inducible factors, HIF-1α and HIF-2α. They in turn induce gene signatures important for survival pathways, like proliferation, glycolysis, angiogenesis, apopotosis suppression, migration and stemness. These changes result in induced proliferative and metastatic processes and such cells contribute to a more aggressive and a resistant phenotype. Importantly, the upregulation of hypoxia inducible angiogenic factors, like Vascular Endothelial Growth Factor (VEGF), from hypoxic sites triggers tumour mass vascularization, called neovascularization. However, the blood vessels thus formed are often poorly organized and dysfunctional, leading to blood clotting and local tissue edema. Thus, niches of hypoxia persist during the growth of solid tumors, selecting for aggressive malignant cells, that contribute to an aggressive phenotype and chemo or radio resistance leading to a poor outcome.
A strong correlation between HIF-1α expression and patient mortality has been observed in many different types of cancers. Also, hypoxia is strongly involved in promoting cancer stemness pathways through various mechanisms, like HIF2 mediated activation of the pluripotency factor, Oct4. It is also observed that increased hypoxia is associated with higher mutation load and genetic instability across cancer types. Also, driver mutations in genes like TP53, PTEN and MYC are found enriched in hypoxic tumors. Thus, hypoxia is a driver of early invasive lesions and it is important to ameliorate the effects of hypoxic microenvironment in order to achieve a better therapeutic response.
Various FDA approved hypoxia targeting/alleviating drugs are available, which are being studied in different clinical trials as combination therapies. These include small molecule HIF1/2, angiogenic inhibitors and hypoxia activated Prodrugs. Recently, immunotherapy has also shown promising results for various cancers. However, it is observed that hypoxic regions, attract immunosuppressive cells and do not retain cytotoxic T cells. Thus, it would become more difficult to target such areas with immunotherapeutic approaches. In such cases, combining hypoxia inhibitors with immune blockers like PDL1, CTLA-4 can lead to better targeting, depending upon the tumor type and its hypoxic status. In spite of detailed understanding of the hypoxic mechanisms, tumor hypoxia has been difficult to target, mainly due to its pleiotropic effects. We hope that easier approaches to identify hypoxic tumor areas and more effective drug delivery mechanisms will help in more effective targeting in future.
