Abstract
Tumour hypoxia is a common feature of solid tumours that contributes to poor prognosis after treatment. This is mainly due to increased resistance of hypoxic cells to radio- and chemotherapy and the association of hypoxic cells with increased metastasis development. It is therefore not surprising that an increased hypoxic tumour fraction is associated with poor patient survival. The extent of hypoxia within a tumour is influenced by the tolerance of individual tumor cells to hypoxia, a feature that differs considerably between tumors. High numbers of hypoxic cells may, therefore, be a direct consequence of enhanced cellular capability inactivation of hypoxia tolerance mechanisms. These include HIF-1α signaling, the unfolded protein response (UPR) and autophagy to prevent hypoxia-induced cell death. Recent evidence shows hypoxia tolerance can be modulated by distant cells that have experienced episodes of hypoxia and is mediated by the systemic release of factors, such as extracellular vesicles (EV). In this review, the evidence for transfer of a hypoxia tolerance phenotype between tumour cells via EV is discussed. In particular, proteins, mRNA and microRNA enriched in EV, derived from hypoxic cells, that impact HIF-1α-, UPR-, angiogenesis- and autophagy signalling cascades are listed.
Highlights
In cancer cells, genetic and epigenetic changes allow uncontrolled growth and proliferation.In addition to these genomic alterations, the tumour microenvironment (TME) is increasingly recognized as an important contributor to cancer progression and therapy resistance [1]
extracellular vesicles (EV)-associated miR-199a derived from bone marrow mesenchymal stromal cells (MSC) protected against I/R damage, potentially by suppression of unfolded protein response (UPR) activation during reperfusion by targeting binding immunoglobulin protein (BiP/GR78) [40]
Besides an ability to transfer ready-to-use molecules to other cells, miRNA’s are able to finetune pathways necessary for cell survival during hypoxia
Summary
Genetic and epigenetic changes allow uncontrolled growth and proliferation. EV-associated miR-199a derived from bone marrow mesenchymal stromal cells (MSC) protected against I/R damage, potentially by suppression of UPR activation during reperfusion by targeting binding immunoglobulin protein (BiP/GR78) [40] These studies implicate EV as important mediators for the transfer of hypoxia tolerance to remote organs. We will review the available evidence on the role of tumour hypoxia on EV cargo and its subsequent effects on the induction of the main hypoxia tolerance mechanisms in target cells, i.e., angiogenesis, HIF-1α signaling, UPR execution and autophagy. Tumour EV were shown to induce the IRE1 branch of the UPR in nonmalignant target cells [22] This was not studied in the context of hypoxia, it suggests that an increased hypoxia-tolerant phenotype could be transmitted by EV through activation of UPR.
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