FIGURE 1.

Formation of the pre-metastatic niche (PMN) in various organs. Extracellular vesicles (EVs) produced by tumor and stromal cells enter the circulation and arrive at distant organs such as the lung, liver, brain, bone marrow, and lymph nodes (LNs). Increased vascular permeability is an early event in PMN formation. Then, EVs cause extracellular matrix (ECM) remodeling principally by activating resident normal fibroblasts. The activated fibroblasts deposit new ECM components, such as FN, and produce matrix metalloproteinases (MMPs). Bone marrow-derived cells (BMDCs) are recruited into the target organs by EVs and involved in angiogenesis and/or immune responses. Furthermore, EVs can deliver their cargos to endothelial cells or immunocytes directly in the PMN to promote angiogenesis or create an immunosuppressive microenvironment.