Hypoxia induced cancer stem cell enrichment promotes resistance to androgen deprivation therapy in prostate cancer

Androgen deprivation therapy (ADT) is the main treatment to prolong survival in advance stage prostate cancer (PCa) but associated resistance leads to the development of terminal castrate resistant PCa (CRPC). Current research demonstrates that prostate cancer stem cells (PCSC) play a critical role in the development of treatment resistance and subsequent disease progression. Despite uncertainty surrounding the origin of these cells, studies clearly show they are associated with poorer outcomes and that ADT significantly enhances their numbers. Here in we highlight how activation of HIF signalling, in response to hypoxic conditions within the tumour microenvironment, results in the expression of genes associated with stemness and EMT promoting PCSC emergence which ultimately drives tumour relapse to CRPC. Hypoxic conditions are not only enhanced by ADT but the associated decrease in AR activation also promotes PI3K/AKT signalling which actively enhances HIF and its effects on PCSC's. Furthermore, emerging evidence now indicates that HIF-2α, rather than the commonly considered HIF-1α, is the main family member that drives PCSC emergence. Taken together this clearly identifies HIF and associated pathways as key targets for new therapeutic strategies that could potentially prevent or slow PCSC promoted resistance to ADT, thus holding potential to prolong patient survival.