Understanding the role of hypoxia and PTEN loss in driving prostate cancer progression
AffiliationCancer Research UK Manchester Institute, Manchester
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AbstractProstate cancer is the most commonly diagnosed cancer in the UK. Increased levels of prostate hypoxia have been shown to drive tumor aggression as an adverse prognostic factor following surgery or radiotherapy, especially when combined with tumor genetic instability. Our recent collaborative bioinformatic studies (Bhandari et al, Nat. Genetics 2019; Nat. Communications 2020) have shown various copy number changes to be enriched in hypoxic tumors, with mono- or bi-allelic loss of the PTEN being the most significant. To delineate a direct relationship between hypoxia and PTEN loss, we interrogated the impact of chronic hypoxia (1% O2, 0.2% O2; 72 h) on PTEN oncogenic signaling and asked whether this translates to improved fitness and survival in non-transformed and transformed PTEN isogenic cell lines. Despite increased oncogenic signaling (increased phospho-AKT) of PTEN-null 22Rv1 cells and hTERT-immortalized prostate epithelial cells (GHM) under chronic hypoxic gassing conditions, this did not lead to increased adaption and tumor clone survival. Differential survival for the PTEN isogenic cell lines following prostate cancer therapies (i.e. IR, PARPi, cDDP, taxols) under oxia and hypoxia are underway to further this work and determine a potential translational importance to clinical treatment. Independent evidence also points to hypoxia/PTEN loss in deregulating centrosome biology as a potential mechanism for genetic instability under hypoxia. Hence, we also hypothesized that the relationship between PTEN and hypoxia might be unearthed if aberrant unstable mitoses following deregulation of spindle poles under hypoxia selectively adapt and have a survival advantage. Quantitative immunofluorescence of centrosome aberrations, using antibodies to phospho-Histone H3 and Centrin-1, show significant increases in centriole numbers (p < 0.05) in mitotic cells under chronic hypoxic conditions and an increase in the incidence of micronuclei (p < 0.005), specifically in chronic hypoxic cells with PTEN loss, supporting our hypothesis. Current studies are investigating in situ staining of centrosomes as a readout of chromosomal instability (CIN) in primary prostate cancer tissues with variable PTEN status as a new biomarker for aggressiveness to link hypoxia-associated genetic instability with novel clinical trial development. (Funded by Cancer Research UK as a core grant to RGB).
CitationSuvac A, Rebello R, Lyons S, Bristow RG. Abstract PO-035: Understanding the role of hypoxia and PTEN loss in driving prostate cancer progression. In: Hypoxia. American Association for Cancer Research; 2021.
JournalClinical Cancer Research
TypeMeetings and Proceedings