University Research Lecturer
Hypoxia and cancer
Our group is focused on the role of hypoxia in cancer using carotid body physiology/pathology as a model system.
Hypoxia is common to many cancers, as the oxygen needs of proliferating tumour cells cannot be met via delivery from local blood vessels. Tumour cells must adapt to this reduced oxygen environment in order to survive. This is in part achieved through hypoxia-induced stabilisation of hypoxia-inducible factor (HIF) - a master transcription factor that activates a massive transcriptional cascade affecting multiple cellular and systemic processes. Many of these processes aid tumour growth, for example metabolic changes including a switch to glycolytic metabolism to support anaerobic ATP production; angiogenesis to support tumour growth and, potentially, metastasis (reviewed in Bishop and Ratcliffe, 2014). In addition, HIF may alter processes such as proliferation and apoptosis that are less obviously concerned with oxygen balance but which may impact tumour growth/survival.
Whilst it is well documented that activation of HIF target genes may facilitate tumour growth, it is less clear whether HIF can initiate cancer per se. The high incidence of genetic mutations in HIF pathway components in tumours provides some evidence for this. For example, von Hippel Lindau (VHL) - one of the major negative regulators of HIF - is a tumour suppressor and patients with germline mutations develop VHL syndrome, a familial cancer syndrome characterised by tumours in a restricted set of tissues: haemangioblastomas (spinal and cerebellar), retinal angioblastomas, renal clear cell carcinomas, phaechromocytomas and carotid paragangliomas. Given the role of VHL in both HIF regulation and as a tumour suppressor, this suggests that activation of HIF could drive tumourigenesis, at least in certain tissues.
Tumours of the adrenal medulla or carotid body, collectively termed phaeochromocytomas/ paragangliomas (PCC/PGL), not only have a high incidence of VHL mutations, but also have been shown to contain a number of gain of function mutations in HIF-2alpha. Further, the carotid body is unique in that hypoxaemia, low arterial oxygen as experienced at altitude or in patients with chronic obstructive pulmonary disease (COPD), induces marked proliferation and overgrowth of the carotid body. This is thought to mediate ventilatory acclimatisation, an increase in ventilation in response to chronic hypoxia that helps redress oxygen balance. In line with this enhanced proliferation, the incidence of carotid body tumours, or carotid body paragangliomas, is ~10x more common at altitude/in COPD. Taken together, this suggests that HIF is capable of initiating tumourigenesis in sympathoadrenal tissues of the carotid body and adrenal medulla, perhaps via stimulation of proliferation.
Using lineage tracing technology and cell-type restricted recombination, our work has shown a cell autonomous role for the PHD2-HIF-2 enzyme-substrate couple in proliferation of Type I cells in the carotid body (Fielding et al., 2018; Hodson et al., 2016). Further, we have developed a mouse model for carotid paraganglioma through inactivation of the principle negative regulator of HIF: HIF prolyl hydroxylase enzyme (PHD)(Fielding et al., 2018). We anticipate that these mice will form a paradigm not only for the study of PGL tumours but also for other ‘pseudohypoxic’ cancers – that is, cancers associated with genetic mutations affecting hypoxia signalling such as renal clear cell carcinoma associated with inherited or sporadic VHL mutations.
Marked and rapid effects of pharmacological HIF-2α antagonism on hypoxic ventilatory control
Cheng X. et al, (2020), Journal of Clinical Investigation, 130, 2237 - 2251
Genetic basis of oxygen sensing in the carotid body: HIF2α and an isoform switch in cytochrome c oxidase subunit 4
Bishop T. and Ratcliffe PJ., (2020), Science Signaling, 13, eaba1302 - eaba1302
Systemic silencing of Phd2 causes reversible immune regulatory dysfunction
Yamamoto A. et al, (2019), Journal of Clinical Investigation, 129, 3640 - 3656
PHD2 inactivation in Type I cells drives HIF‐2α‐dependent multilineage hyperplasia and the formation of paraganglioma‐like carotid bodies
Fielding JW. et al, (2018), The Journal of Physiology, 596, 4393 - 4412
Hypoxia-inducible factor 1-alpha does not regulate osteoclastogenesis but enhances bone resorption activity via prolyl-4-hydroxylase 2
Hulley PA. et al, (2017), The Journal of Pathology, 242, 322 - 333