Exosomes in the hypoxic TME: from release, uptake and biofunctions to clinical applications

Abstract

Hypoxia is a remarkable trait of the tumor microenvironment (TME). When facing selective pressure, tumor cells show various adaptive characteristics, such as changes in the expression of cancer hallmarks (increased proliferation, suppressed apoptosis, immune evasion, and so on) and more frequent cell communication. Because of the adaptation of cancer cells to hypoxia, exploring the association between cell communication mediators and hypoxia has become increasingly important. Exosomes are important information carriers in cell-to-cell communication. Abundant evidence has proven that hypoxia effects in the TME are mediated by exosomes, with the occasional formation of feedback loops. In this review, we equally focus on the biogenesis and heterogeneity of cancer-derived exosomes and their functions under hypoxia and describe the known and potential mechanism ascribed to exosomes and hypoxia. Notably, we call attention to the size change of hypoxic cancer cell-derived exosomes, a characteristic long neglected, and propose some possible effects of this size change. Finally, jointly considering recent developments in the understanding of exosomes and tumors, we describe noteworthy problems in this field that urgently need to be solved for better research and clinical application.

Fig. 1

A schematic representation for the biological process of exosomes and key steps affected by hypoxia. ①Hypoxia affects cargo synthesis at translation level. ②Hypoxia influence exosome release and cargo-sorting by cargo-loading key tools (such as YBX1 and hnRNPA1). ③Hypoxia blocks MVBs degradation to increase exosome release (such as downregulating Rab7). ④Hypoxia causes overexpression of key molecules involving in MVBs transport towards plasma membrane to increase exosome release (such as Rab27). ⑤Hypoxia may increase exosome release by promoting the fusion between MVBs and plasma membrane (such as SNARE protein). ⑥Intercellular transport includes long-distance transport to distant recipient cells by circulation system (left) short-distance transport in local TME (right). Smaller exosome size induced by hypoxia seems to facilitate circulation transport, but it is not been proved. Acidic microenvironment, a result of hypoxia, may be beneficial to transport under local acidic microenvironment. ⑦Hypoxia and low-pH can increase exosome uptake efficiency. It has been proved that membrane composition changed by low-pH influence exosome uptake by homologous cells, but it was not explored under hypoxia. It remains unknown that which of exosome uptake methods is more obviously changed by hypoxia

Fig. 2

The heterogeneities of exosomes and their biofunction in the hypoxic TME. Different colors for cells represent different kinds and status (such as hypoxia) of cells in tumour microenvironment, indicating tumour heterogeneities. Different colors for exosomes represent heterogeneities in exosomal cargoes and cellular origins. Similar colors between cells and exosomes represent heterogeneities in exosomal origin. Different diameters represent heterogeneities in exosomal size. The outer circle of the picture represents the hallmarks of cancer. Red arrowhead represents that hypoxic tumour-derived exosomes influence corresponding cancer hallmarks and these arrowheads indicate heterogeneities in biofunctions medicated by exosomes. Blue dotted line represents it is too early to draw a conclusion that corresponding hallmarks are affected by hypoxic tumour-derived exosomes [190]