RESUMEN
Hypoxia promotes tumour aggressiveness and resistance of cancers to oncological treatment. The identification of cancer cell internalizing antigens for drug targeting to the hypoxic tumour niche remains a challenge of high clinical relevance. Here we show that hypoxia down-regulates the surface proteome at the global level and, more specifically, membrane proteome internalization. We find that hypoxic down-regulation of constitutive endocytosis is HIF-independent, and involves caveolin-1-mediated inhibition of dynamin-dependent, membrane raft endocytosis. Caveolin-1 overexpression inhibits protein internalization, suggesting a general negative regulatory role of caveolin-1 in endocytosis. In contrast to this global inhibitory effect, we identify several proteins that can override caveolin-1 negative regulation, exhibiting increased internalization at hypoxia. We demonstrate antibody-mediated cytotoxin delivery and killing specifically of hypoxic cells through one of these proteins, carbonic anhydrase IX. Our data reveal that caveolin-1 modulates cell-surface proteome turnover at hypoxia with potential implications for specific targeting of the hypoxic tumour microenvironment.
Asunto(s)
Antígenos de Neoplasias/genética , Anhidrasas Carbónicas/genética , Caveolina 1/genética , Dinaminas/genética , Regulación Neoplásica de la Expresión Génica , Animales , Anticuerpos/química , Anticuerpos/farmacología , Antígenos de Neoplasias/metabolismo , Anhidrasa Carbónica IX , Anhidrasas Carbónicas/metabolismo , Caveolas/efectos de los fármacos , Caveolina 1/metabolismo , Hipoxia de la Célula , Línea Celular Tumoral , Toxina del Cólera/química , Toxina del Cólera/farmacología , Dinaminas/metabolismo , Fibroblastos/citología , Fibroblastos/metabolismo , Perfilación de la Expresión Génica , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Inmunoconjugados/química , Inmunoconjugados/farmacología , Ratones , Transporte de Proteínas/efectos de los fármacos , Proteoma/genética , Proteoma/metabolismo , Transducción de SeñalRESUMEN
Exosomes and microvesicles, collectively referred to as extracellular vesicles (EVs), can transfer complex biological information and induce a diverse signalling response in recipient cells with potential relevance in a wide array of pathological conditions. Tissue hypoxia constitutes a stress-associated phenotype that is central to the malignant state of aggressive tumours as well as to ischaemic tissue in cardiovascular disorders. The adaptive response to hypoxic stress is largely dependent on intercellular communication in which EVs, and cellular exchange of EV cargo molecules, have recently been implicated. The results of numerous studies indicate that hypoxia-dependent shaping of the molecular profile of EVs may mediate the biological response to hypoxia. EVs have been shown to induce tumour angiogenesis and hypercoagulation as well as tissue remodelling and protective effects in ischaemic cardiovascular conditions. Recent findings report increased levels of circulating EVs in patients with hypoxia-associated disorders such as myocardial infarction, stroke and pre-eclampsia, indicating a role of EVs as biomarkers in these pathophysiological states. Here, we discuss the intriguing role of EVs in tumour development and cardiovascular disease, focusing on the paracrine transfer of the hypoxic response to neighbouring cells and to distant cells at the systemic level, with wide implications for biomarker discovery and therapeutic intervention.
