Deciphering the role of ectosomes in cancer development and progression: focus on the proteome

Abstract

Ectosomes are small heterogeneous membrane vesicles generated by budding from the plasma membrane in a variety of cell types and, more frequently, in tumor cells. They are shed into the extracellular space and are proposed as a novel form of intracellular communication in which information is transmitted from the originating cell to recipient cells without direct cell-to-cell contact. This review focuses on a single population of extracellular vesicles-ectosomes. We summarize recent studies of tumor-derived ectosomes which examine their biogenesis and protein cargo, and their influence on different aspects of cancer progression. We discuss possible clinical implications involving ectosomes as potential biomarkers, diagnostic tools and treatment targets in oncology. The unique composition of the molecules (cargo) that ectosomes carry, and their functional role, depends largely on the state of their originating cell. Through horizontal transfer of a variety of biologically active molecules (including proteins, lipids and nucleic acids) between donor and recipient cells, tumor-derived ectosomes may play functional roles in oncogenic transformation, tumor progression, invasion, metastasis, angiogenesis promotion, escape from immune surveillance, and drug resistance, thereby facilitating disease progression. The presence of tumor-derived ectosomes in body fluids such as the blood and urine of cancer patients makes them potentially useful prognostic and predictive biomarkers. Tumor-derived ectosomes also offer possible targets for multiple therapeutic strategies.

Keywords: Cancer; Ectosomes; Immunosuppression; Intracellular communication; Multidrug resistance; Tumor microenvironment.

Fig. 1

Representative images of extracellular vesicles released from tumor cells. a Exosomes from urine of diabetic patients (transmission electron microscopy, TEM), b ectosomes from human melanoma WM1205Lu cells (TEM), c apoptotic bodies from human acute lymphoblastic leukemia MOLT-4 cells (May-Grűnwald-Giemsa staining)

Fig. 2

Examples of ectosome cargo. ARF6: ADP-ribosylation factor 6, CD40: cluster of differentiation 40, EGFR: epidermal growth factor receptor, EMMPRIN: extracellular matrix metalloproteinase inducer, IL-1β: interleukin 1β, LAMP-1: lysosomal-associated membrane protein 1, MMP: matrix metalloproteinase, uPA: urokinase plasminogen activator, VAMP-3: vesicle-associated membrane protein 3, VEGF: vascular epithelium growth factor

Fig. 3

Mechanisms responsible for ectosome blebbing and release. Ectosomes are generated by outward budding and fusion of the plasma membrane, but their membrane composition is distinct from that of parental cells. Alterations of phospholipid symmetry are governed by aminophospholipid translocases (flippase and floppase) and Ca²⁺-dependent scramblase. Ectosomes are enriched in cholesterol, whereas phosphatidylserine (PS) is exposed on the extracellular leaflet of shed ectosomes. Cytoskeletal reorganization upon ectosome release is induced by calpain and gelsolin, although alternative mechanisms in cancer cells have been described, including RhoA [37] or ARF6 [14, 15] and their effectors. ARF6: ADP-ribosylation factor 6, ERK: extracellular signal-regulated kinase, LIMK: LIM domain kinase, MLCK: myosin light chain kinase, RhoA: Ras homolog gene family member A, ROCK: Rho-associated protein kinase

Fig. 4

Role of tumor ectosomes in key pathways promoting cancer progression through interaction with local and distant cells