Cancer cells thrive within a complex milieu characterized by hypoxia that plays a fundamental role in tumor development. Altogether, hypoxic stress-induced signalling select for tumor cells that will successfully adapt to their hostile microenvironment and drive disease progression by inducing, for example, angiogenesis, immune cell evasion, coagulation and cancer cell stemness. These responses further result in resistance to conventional cancer therapies, including radiotherapy and chemotherapy. An increased understanding of cancer cell adaptive mechanisms to hypoxia is critical for the development of improved strategies in the fight against cancer.
Abnormal trafficking of cell-surface receptors is involved in malignant transformation, and several endocytosis associated proteins are deregulated in cancer cells. Accumulating evidence indicates that cellular responses to the extracellular environment are regulated by the spatial coordination of cell-surface proteins and further uptake and sorting into vesicular compartments of the endocytic systems.
Interestingly, in some cases these mechanisms have been related to hypoxia, thereby contributing to an enhanced tumorigenic signalling. Accordingly, cell-surface receptors with endocytic transport activity emerge as attractive targets for tumor-specific delivery of therapeutic substances, most importantly antibody-drug conjugates (ADCs) that are currently approved in the treatment of breast cancer and lymphoma.
The overall effects of hypoxia on the cellular transcriptome, proteome and metabolome have been extensively studied, pointing at a diverse and relatively conserved response in malignant tumors of different origins. Researchers implemented a widely applicable method that integrates reversible membrane protein labelling with fluorescence-activated cell sorting (FACS), confocal microscopy imaging and quantitative proteomics analyses for the comprehensive visualization, quantification and identification of internalizing cell-surface proteins.
They show that hypoxia down-regulates the surface proteome at the global level and, more specifically, membrane proteome internalization. Authors 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, authors identify several proteins that can override caveolin-1 negative regulation, exhibiting increased internalization at hypoxia.
They demonstrate antibody-mediated cytotoxin delivery and killing specifically of hypoxic cells through one of these proteins, carbonic anhydrase IX. The data reveal that caveolin-1 modulates cell-surface proteome turnover at hypoxia with potential implications for specific targeting of the hypoxic tumor microenvironment.