Understanding and controlling extracellular vesicle-mediated cancer-host crosstalk in the body

Intercellular communication is an essential event of multicellular organisms and can be mediated through cell-cell contact or transfer of secreted molecules. The ability of a cell to receive signals from other cells plays crucial roles in development and tissue homeostasis. However, deregulation of these orchestrated cell-to-cell communication causes onset or progression of diseases. Recently a third mechanism for cell-to-cell communication that involves extracellular vesicles (EVs) has emerged. It has been shown that various biomolecules including surface membrane, proteins, DNAs, mRNAs, and noncoding RNAs are exchanged among neighboring or distant cells via EVs. At present, 3 main types of EV are recognized according to their biogenesis: exosome, microvesicle (MV), and apoptotic body (AB). Exosomes are small vesicles (40 – 120 nm in diameter) secreted from endosomal compartments called multivesicular bodies (MVB). Their biogenesis begins with intraluminal vesicle (ILV) formation by inward budding of the MVB membrane. Three tetraspanins (CD63, CD81, CD9) are identified as exosome markers, and several intracellular proteins (e.g., Rab GTPase, Alix, Tsg101) are required for exosome biogenesis and secretion. MVs are larger vesicles (50 – 1000 nm in diameter) created through direct budding from the plasma membrane accompanying cytoskeletal remodeling. ABs are also larger vesicles (500 – 2000 nm in diameter) that are released by cells undergoing apoptosis and may contain nuclear fragments.

In the tumor microenvironment, populations of genetically and epigenetically diverse cancer cells interact with stromal cells such as fibroblasts, endothelial cells, and infiltrating immune cells in cancer progression. Recent studies have revealed that cancer-associated EVs have key roles in angiogenesis induction, control of cellular invasion, initiation of pre-metastatic niches, maintenance of inflammation, and evasion of immune surveillance through cell-to-cell communication between cancer and normal cells.

The Kanada lab focuses on understanding extracellular vesicle (EV)-mediated cancer-host crosstalk in the body. We are developing multiscale imaging approaches to determine how EVs impact different aspects of cancer progression. As potential therapeutic agents, EVs offer advantages of possessing inherent tissue penetrating characteristics and overcoming immune rejection. We are also creating EV-based gene delivery vehicles as a new cancer gene therapy approach.