Exosomes in cancer theranostic: Diamonds in the rough

Abstract

During the last 10 years, exosomes, which are small vesicles of 50-200 nm diameter of endosomal origin, have aroused a great interest in the scientific and clinical community for their roles in intercellular communication in almost all physiological and pathological processes. Most cells can potentially release these nanovesicles that share with the parent cell a similar lipid bilayer with transmembrane proteins and a panel of enclosed soluble proteins such as heat shock proteins and genetic material, thus acting as potential nanoshuttles of biomarkers. Exosomes surface proteins allow their targeting and capture by recipient cells, while the exosomes' content can modify the physiological state of recipient cells. Tumor derived exosomes by interacting with other cells of the tumor microenvironment modulate tumor progression, angiogenic switch, metastasis, and immune escape. Targeting tumor-derived exosomes might be an interesting approach in cancer therapy. Furthermore, because a key issue to improve cancer patients' outcome relies on earlier cancer diagnosis (metastases, as opposed to the primary tumor, are responsible for most cancer deaths) exosomes have been put forward as promising biomarker candidates for cancer diagnosis and prognosis. This review summarizes the roles of exosomes in cancer and clinical interest, focusing on the importance of exosomal heat shock proteins (HSP). The challenges of clinical translation of HSP-exosomes as therapeutic targets and biomarkers for early cancer detection are also discussed.

Keywords: cancer diagnosis; cancer therapy; exosomes; heat shock proteins.

Figure 1.

Scheme of exosomes biogenesis, composition and internalization. Biogenesis: the biogenesis of exosomes involves 4 different steps: (1) the membrane invagination; (2) endosome formation; (3) generation of the exosomes precursors, called intraluminal vesicles (ILVs), by inward budding of endosomes. These accumulations of ILVs is termed as multivesicular bodies (MVBs); (4) the fusion of MVBs with the plasma membrane release the ILVs in the extracellular space by exocytosis and become exosomes. Composition: Exosome are composed by different types of enzymes and proteins involved in: adhesion, traffic, intracellular signaling, immunostimulatory molecules, multivesicular body (MVB) formation and heat shock proteins (HSPs). Exosomes contain lipids such as (I) saturated phospholipids (phosphatidyl-ethanolamine, glycero-phospholipids, phosphatidyl-choline and phosphatidyl-serine) (ii) sphingolipids (ceramides), (iii) cholesterol. Finally, exosomes contain nucleic acids, including miRNA, mRNA, DNA and small non coding RNA (snRNA, tRNA). Internalization : The exosome may, (i) elicit transduction of the signal via intracellular signaling pathways by direct contact through adhesion molecules like integrin or through a ligand-receptor interaction, (ii) be endocytosed via phagocytosis, macropinocytosis or receptor-mediated endocytosis, or (iii) fusion with the plasma membrane and transfer its content into the cytoplasm of the recipient cell.

Figure 2.

Exosomal heat shock proteins: theranostic oncology tools. HSP60 and HSP70 are proposed as potential cancer biomarkers because of their presence only in exosomes derived from cancer cells. Exosomal HSP70 can act in 2 different ways in the modulation of the immune system. Indeed, it can play an immunosuppressive role through the activation of MDSCs that block the anti-tumor response. But it can have an opposite effect by activating immune cells such as macrophages, dendritic cells (DC) or natural killer cells (NK) which may lead to anti-tumor response. Furthermore, HSP90 may represent a therapeutic target because of their ability to respectively increase tumor cell motility (activation of plasmin tPA).