Abstract
Simple SummaryHuman cells can communicate with each other by releasing small packets of protein called ‘vesicles’ that are absorbed by other cells nearby and at distant locations, leading to major changes in biological activity. This is also the case for cancer cells within developing tumours, which become starved of oxygen when they outgrow local blood supplies. We wondered whether oxygen starvation might cause cancer cells to alter the protein cargo they package into vesicles, which could play an important role in supporting further tumour development. We found that under oxygen-starved conditions, cancer cells release far higher numbers of vesicles that are actively packed with proteins known to enhance tumour survival, support distribution to other body sites, and suppress patient immune responses. Cancer vesicles could therefore be used to develop new diagnostic tests that inform doctors about disease progression, and may also represent useful drug targets for new types of patient treatment.Extracellular vesicles (EVs) mediate critical intercellular communication within healthy tissues, but are also exploited by tumour cells to promote angiogenesis, metastasis, and host immunosuppression under hypoxic stress. We hypothesize that hypoxic tumours synthesize hypoxia-sensitive proteins for packing into EVs to modulate their microenvironment for cancer progression. In the current report, we employed a heavy isotope pulse/trace quantitative proteomic approach to study hypoxia sensitive proteins in tumour-derived EVs protein. The results revealed that hypoxia stimulated cells to synthesize EVs proteins involved in enhancing tumour cell proliferation (NRSN2, WISP2, SPRX1, LCK), metastasis (GOLM1, STC1, MGAT5B), stemness (STC1, TMEM59), angiogenesis (ANGPTL4), and suppressing host immunity (CD70). In addition, functional clustering analyses revealed that tumour hypoxia was strongly associated with rapid synthesis and EV loading of lysosome-related hydrolases and membrane-trafficking proteins to enhance EVs secretion. Moreover, lung cancer-derived EVs were also enriched in signalling molecules capable of inducing epithelial-mesenchymal transition in recipient cancer cells to promote their migration and invasion. Together, these data indicate that lung-cancer-derived EVs can act as paracrine/autocrine mediators of tumorigenesis and metastasis in hypoxic microenvironments. Tumour EVs may, therefore, offer novel opportunities for useful biomarkers discovery and therapeutic targeting of different cancer types and at different stages according to microenvironmental conditions.
Highlights
Oxygen deprivation or ‘hypoxia’ is a characteristic environmental stress experienced by cancer cells within solid tumours
We identified a group of hypoxia-sensitive extracellular vesicles (EVs) proteins (HSEPs) that may play a critical role in stimulating epithelial–mesenchymal transition (EMT) and metastasis within the local microenvironment
EVs are released by hypoxic tumour cells into the local microenvironment to modulate its survival but the effect of tumour hypoxia on the dynamics of protein synthesis and loading into EVs remains unclear
Summary
Oxygen deprivation or ‘hypoxia’ is a characteristic environmental stress experienced by cancer cells within solid tumours. In order to adapt to low-oxygen conditions, tumour cells activate the hypoxia-inducible factor (HIF) pathway which drives the expression of genes that promote angiogenesis, support cell growth and proliferation, and enhance migration and tissue invasion [1]. Cancer cell adaptation to hypoxia stress is associated with a more aggressive phenotype as well as increased resistance to treatment with chemotherapy and radiotherapy [2]. A better understanding of tumour cell responses to hypoxia stress will be essential to developing more effective therapies to overcome tumour progression and treatment resistance. Exosomes in particular have been shown to play major roles in intercellular communication by the direct transfer of functionally active biomolecules including proteins and nucleic acids into the cytosol of recipient cells [5]. Investigators have begun to appreciate that EVs play a crucial role in the development of cancer via the induction of angiogenesis, ability to suppress host immunity [3,6,7], and promotion of epithelial–mesenchymal transition (EMT)
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