Exosomes and tunneling nanotube conduits: Synergistic interaction that facilitates intercellular communication between malignant and stromal cells in the tumor microenvironment

Extracellular vesicles-including exosomes-facilitate long-range intercellular communication in cancer. These membrane-lined vesicles are diffusible carriers of vital cellular signals that can alter the phenotype of recipient cells. However, they are not the only mediator of long-range intercellular cross talk in the complex and heterogeneous tumor microenvironment. Tunneling nanotubes (TNTs) and tumor microtubes are long, thin, filamentous actin-based cell extensions formed by cancer cells to create direct pipeline-like connections that also mediate direct intercellular signaling. Exosomes and TNTs can, in fact, act synergistically: tumor-derived exosomes stimulate the formation of TNTs in cancer, and in turn TNTs can serve as direct physical conduits for cell-to-cell transport of exosomes and their contents. Here, we will examine the interface of exosomes and TNTs; discuss how they work together rather than in isolation; review physiologic conditions that enhance their formation; and explore common mechanisms and markers of formation that serve as potential therapeutic targets.