Hypoxia is a common phenomena in solid tumours where functionally and structurally disturbed microcirculation as well as the deterioration of diffusion conditions leads to formation on hypoxic centers within tumours. Tumour hypoxia is strongly associated with tumour propagation, malignant progression and resistance to therapy and as such it has become a central issue in tumour physiology and cancer treatment.
Prostate cancer deposits exist within a hypoxic environment. Hypoxia is a major factor in prostate cancer aggressiveness and radioresistance and is caused by inadequate supply of oxygen (O2) leading to tissue hypoxia and compromising biological functions.
In prostate cancer, ninety percent of prostate cancer patients are diagnosed with localized carcinoma, which have a highly variable course of disease progression. Localized prostate cancer has marked and heterogeneous hypoxia and hypoxia is an adverse prognostic feature. The local disease is managed with combinations of surgery, radiotherapy and hormones but the presence of hypoxia increases treatment resistance in prostate cancer patients treated with surgery or radiotherapy.
From metabolic point of view it is well established that prostate cancer cells depend on enhanced glucose transport and glycolysis for expansion, whereas growth is contingent with neovascularization to permit diffusion of oxygen and glucose. Hypoxia inducible factor 1 alpha (HIF-1α) remains the central player but also other molecules and pathways are affected and activated, all positively correlated with the degree of intratumoral hypoxia.
HIF-1 is a major regulator of the cell's response to a hypoxic microenvironment, which is strictly controlled through synthesis, and degradation. Hypoxia and overexpression of HIF-1 may be related to radiotherapy and chemotherapy resistance, increased risk of tumor invasion and metastasis, and poor clinical prognosis of most solid tumors, and especially so in PCa; therefore, the HIF-1 pathway is considered as a viable pharmacological target in the treatment of solid tumors. Hypoxia has been linked to cancer progression, recurrence, and metabolic reprogramming. Under hypoxic conditions, HIF-prolyl hydroxylases (PHDs) activity is inhibited, HIF-1a accumulates, and dimerizes with HIF-1b, thereby activating transcription of hundreds of genes. The prevalence of hypoxia and the increase in HIF-1α have raised interest in targeting the HIF pathway for most solid tumors. Recent evidence from genetic and pharmacological research supports the view that inhibition of HIF-1 is beneficial for cancer treatment.
Growing evidence has linked prostate cancer carcinogenesis with early loss of cellular protection to oxidative damage, participating in increased DNA damage and genetic instability. Cellular respiration and the production of ATP is inevitably one of the first to suffer from oxygen deprivation and results in the production of reactive oxygen species (ROS).
Reprogramming of cellular metabolism is profoundly implicated in tumorigenesis and can be exploited to cancer treatment. Cancer cells are known for their propensity to use glucose-dependent glycolytic pathway instead of mitochondrial oxidative phosphorylation for energy generation even in the presence of oxygen, a phenomenon known as Warburg effect. For instance, type II beta regulatory subunit of protein kinase A (PKA), PRKAR2B, is highly expressed in castration-resistant prostate cancer (CRPC) and contributes to tumour growth and metastasis. HIF-1 is the key transcription factor responsible for inducing PRKAR2B expression in prostate cancer. Importantly, inhibition of glycolysis by the glycolytic inhibitor 2- deoxy-d-glucose (2-DG) or replacement of glucose in the culture medium with galactose (which has a much lower rate than glucose entry into glycolysis) largely compromised PRKAR2B-mediated tumour-promoting effect. Similar phenomenon was noticed by genetic silencing of HIF-1.
In summary, prostate cancer, like all other solid tumour -forming cancers have hypoxic regions within the tumour mass. These are the areas that harbour radioresistant cells with altered metabolic activity. By conducting research in vitro in similar conditions that cells are in vivo is the only way to really mimic and understand these events. Through understanding they can be utilized in designing more efficient therapeutics.
‘Development and validation of a 28-gene hypoxia-related prognostic signature for localized prostate cancer’ (Yang et al., 2018 EBioMedicine)
‘Hypoxia in prostate cancer: A powerful shield against tumour destruction?’ (Marignol et al., 2008 Cancer Treatment Reviews)
‘Tumor hypoxia predicts biochemical failure following radiotherapy for clinically localized prostate cancer’ (Milosevic et al., 2012 Clinical Cancer Research)
‘PRKAR2-HIF-1a loop promotes aerobic glycolysis and tumour growth in prostate cancer’
(Xia et al., 2020 Cell Proliferation)