Bad neighbours: hypoxia and genomic instability in prostate cancer

Abstract

Prostate cancer (PCa) is a clinically heterogeneous disease and has poor patient outcome when tumours progress to castration-resistant and metastatic states. Understanding the mechanistic basis for transition to late stage aggressive disease is vital for both assigning patient risk status in the localised setting and also identifying novel treatment strategies to prevent progression. Subregions of intratumoral hypoxia are found in all solid tumours and are associated with many biologic drivers of tumour progression. Crucially, more recent findings show the co-presence of hypoxia and genomic instability can confer a uniquely adverse prognosis in localised PCa patients. In-depth informatic and functional studies suggests a role for hypoxia in co-operating with oncogenic drivers (e.g. loss of PTEN) and suppressing DNA repair capacity to alter clonal evolution due to an aggressive mutator phenotype. More specifically, hypoxic suppression of homologous recombination represents a “contextual lethal“ vulnerability in hypoxic prostate tumours which could extend the application of existing DNA repair targeting agents such as poly-ADP ribose polymerase inhibitors. Further investigation is now required to assess this relationship on the background of existing genomic alterations relevant to PCa, and also characterise the role of hypoxia in driving early metastatic spread. On this basis, PCa patients with hypoxic tumours can be better stratified into risk categories and treated with appropriate therapies to prevent progression.

Hyperpolarised 13C-MRI identifies the emergence of a glycolytic cell population within intermediate-risk human prostate cancer

“…This finding is underpinned by cell-specific expression of the monocarboxylate transporters 1 and 4 (MCT1/4), where MCT1 and MCT4 are expressed mostly on tumour and stromal cells respectively and mediate lactate/pyruvate influx (MCT1) and lactate efflux (MCT4) 28 , 31 , 32 . In contrast, aggressive prostate tumours and metastatic lesions demonstrate higher glycolytic flux, driven partly by hypoxia-induced upregulation of glycolytic enzymes 33 , and partly by the metabolic reprogramming that results from genomic abnormalities, such as loss of PTEN 34 , 35 . Therefore, higher glycolytic flux in high-grade tumours 36 might explain the increased [1- 13 C]lactate labelling in aggressive disease compared to more oxidative early-stage lesions.…”

A Humanized Monoclonal Antibody Targeting Extracellular Nicotinamide Phosphoribosyltransferase Prevents Aggressive Prostate Cancer Progression

“…Current mechanistic concepts for this PCa transition to aggressive, metastatic CRPC have highlighted the involvement of a hypoxic tumor environment, inflamed peri-prostatic adipose tissues, and inflammatory signaling pathways that activate androgen receptors and promote PCa progression. It is well known that the hypoxic tumor microenvironment results in hypoxia-induced transcription factors (HIF-1α, HIF-2α)-mediated production of locally produced chemokines/cytokines [26][27][28][29][30] emanating from normal prostate epithelial cells, periprostatic adipocytes, and PCa cells. Thus, a novel therapy that targets inflammatory signaling pathways may represent a potent mechanism to prevent PCa progression and to reduce PCa lethality.…”

Impact of Lineage Plasticity to and from a Neuroendocrine Phenotype on Progression and Response in Prostate and Lung Cancers

“…Our model suggests the additional potential of genetic instability-directed or hypoxia-directed therapy to offset lineage changes and resistance in prostate and lung SCCs (Ashton and Bristow, 2020;Borst et al, 2017;DiGiacomo and Gilkes, 2019;Lin et al, 2017;Salem et al, 2018). Our preclinical work supported the use of PARP inhibition in the DDR-deficient hypoxic tumor cells based on an acquired BRCAness which led to increased sensitivity to Olaparib, both in vitro and in vivo (reviewed in Ashton and Bristow, 2020). The clinical success of PARP inhibitors in PCa with germline and acquired mutations in BRCA2 and ATM lays the groundwork for their use in the hypoxic setting to prevent lineage plasticity (Gillessen and Bristow, 2020).…”

“…The 2019 Nobel Prize in Medicine was awarded to scientists who unraveled the effect of oxygen delivery and metabolism in normal and malignant tissues. All solid tumors, including lung and prostate cancers and their metastases, contain sub-regions of abnormal cell metabolism that can result from dynamic and differential gradients of oxygen consumption within the TME (Ashton and Bristow, 2020;Bhandari et al, 2019;Bharti et al, 2019). Tumor adaptation to imbalanced oxygen supply and demand is associated with poor prognosis and elevated genomic instability, resistance to chemotherapy and radiotherapy, immune dampening, altered autophagy, development of tumor stem cell protective niches, and increased proclivity for distant metastasis, such as bone metastases (Bristow and Hill, 2008;Johnson et al, 2017;Luoto et al, 2013;Nobre et al, 2018).…”

“…More work is needed to understand further changes in genomics in hypoxic metastases in samples collected from metastatic treatment-sensitive and treatment-resistant cancers. We speculate that hypoxia-induced drug resistance observed following both non-targeted and targeted drug treatments (Jing et al, 2019;Ye et al, 2019) leads to further clonal adaption and increasing chromosomal instability (CIN) resulting in acquired resistance and SCC plasticity changes (Ashton and Bristow, 2020;Luoto et al, 2013). This is based on observations that hypoxia can modify the DNA damage response (DDR), and, in some cases, hypoxic cells are rendered DNA repair deficient (Chan et al, 2010).…”