Regulation of lymphangiogenesis by extracellular vesicles in cancer metastasis

Metastasis is not only one of the hallmarks of cancer but, unfortunately, it also is the most accurate biomarker for poor prognosis. Cancer cells metastasize through two different but eventually merged routes, the vasculature and lymphatic systems. The processes of cancer metastasis through blood vessel have been extensively studied and are well documented in the literature. In contrast, metastasis through the lymphatic system is less studied. Most people believe that cancer cells metastasize through lymphatic vessel are passive because the lymphatic system is thought to be a sewage draining system that collects whatever appears in the tissue fluid. It was recently found that cancer cells disseminated from lymphatic vessels are protected from being destroyed by our body's defense system. Furthermore, some cancer cells or cancer-associated immune cells secrete lymphangiogenic factors to recruit lymphatic vessel infiltration to the tumor region, a process known as lymphangiogenesis. To ensure the efficiency of lymphangiogenesis, the lymphangiogenic mediators are carried or packed by nanometer-sized particles named extracellular vesicles. Extracellular vesicles are lipid bilayer particles released from eventually every single cell, including bacterium, with diameters ranging from 30 nm (exosome) to several micrometers (apoptotic body). Components carried by extracellular vesicles include but are not limited to DNA, RNA, protein, fatty acid, and other metabolites. Recent studies suggest that cancer cells not only secrete more extracellular vesicles but also upload critical mediators required for lymphatic metastasis onto extracellular vesicles. This review will summarize recent advances in cancer lymphatic metastasis and how cancer cells regulate this process via extracellular vesicle-dependent lymphangiogenesis.