Molecular Determinants Involved in the Docking and Uptake of Tumor-Derived Extracellular Vesicles: Implications in Cancer

Abstract

Extracellular vesicles produced by tumor cells (TEVs) influence all stages of cancer development and spread, including tumorigenesis, cancer progression, and metastasis. TEVs can trigger profound phenotypic and functional changes in target cells through three main general mechanisms: (i) docking of TEVs on target cells and triggering of intra-cellular signaling; (ii) fusion of TEVs and target cell membranes with release of TEVs molecular cargo in the cytoplasm of recipient cell; and (iii) uptake of TEVs by recipient cells. Though the overall tumor-promoting effects of TEVs as well as the general mechanisms involved in TEVs interactions with, and uptake by, recipient cells are relatively well established, current knowledge about the molecular determinants that mediate the docking and uptake of tumor-derived EVs by specific target cells is still rather deficient. These molecular determinants dictate the cell and organ tropism of TEVs and ultimately control the specificity of TEVs-promoted metastases. Here, we will review current knowledge on selected specific molecules that mediate the tropism of TEVs towards specific target cells and organs, including the integrins, ICAM-1 Inter-Cellular Adhesion Molecule), ALCAM (Activated Leukocyte Cell Adhesion Molecule), CD44, the metalloproteinases ADAM17 (A Disintegrin And Metalloproteinase member 17) and ADAM10 (A Disintegrin And Metalloproteinase member 10), and the tetraspanin CD9.

Keywords: ADAM10; ADAM17; ALCAM/CD166; CD44; CD9; ICAM-1/CD54; TEV docking; TEV uptake; adhesion receptors; integrins; tetraspanins; tumor-derived extracellular vesicles (TEVs).

Figure 1

EVs released from donor cells include microvesicles and exosomes. These EVs carry a cargo of biomolecules (proteins, nucleic acids, and lipids) and can induce phenotypic and functional changes in target recipient cells through different general mechanisms. These include ligand-receptor mediated docking and subsequent intracellular signaling, membrane fusion, and EV uptake through macropinocytosis, phagocytosis, caveolin-, clathrin-, or lipid raft-dependent endocytosis.

Figure 2

Differential integrin expression can mediate TEVs docking, uptake, and tropism. The presence of integrins on TEVs surface can guide their tropism or mediate their interaction and/or uptake with different target cells via ligand interaction. (A) Differential integrin expression profiles on TEVs surface can determine tissue organotropism. Integrins α6β1 and α6β4 on TEVs surface mediate lung-tropic metastasis; αVB5 mediates liver-tropic metastasis and the presence of α4 and/or β4 integrins usually correlates with TEV selectivity to endothelium, pancreas fibroblasts or lymph node stroma. (B) Some TEVs present a fibronectin coat on their surface when α5β1 integrins or Heparansulfate Proteoglicans (HSPGs) are present on their membranes. This fibronectin coat on TEVs mediates their docking to target cells via interaction with α5β1 integrins on the surface of target cells. (C) The presence of β2 integrins, such as LFA-1 or Mac-1, on the surface of immune target cells facilitates the docking of ICAM-1-surface-presenting TEVs.

Figure 3

Roles of ADAM17 and tetraspanin CD9 in the targeting and docking of TEVs. (A) ADAM17 can influence the docking and targeting of TEVs to target cells through its dual role: (i) as an adhesion ligand that engages in cis and trans interactions with integrins; and (ii) as a sheddase that releases the ectodomains of its multiple transmembrane substrates, thus controlling the levels of many adhesive proteins on the surface of both TEVs and target cells. (B) Tetraspanin CD9 influences the activity of different adhesion receptors through a triple mechanism that involves the following: (i) augmented clustering of receptors on the cell and/or TEVs surface with resulting increase in their avidity; (ii) upregulation of the expression of ADAM17 transmembrane substrates on the surface of cells and TEVs due to CD9-mediated inhibition of ADAM17 sheddase activity; and (iii) inhibition of trans α5β1/ADAM17 adhesive interactions through imposition of unfavorable conformational changes on these molecules.