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Figure 2. The systemic effects of extracellular vesicles and particles (EVPs) in cancer. EVPs can transport various biomolecules to distant organs. EVP uptake by specific cells in the microenvironment of the remote organ results in functional reprograming of target cells. For example, tumor-derived EVPs can promote angiogenesis and vascular remodeling, modify the extracellular matrix (ECM), promote lymphangiogenesis, modulate the function of immune cells to create an immunosuppressive environment, and reprogram metabolism. Moreover, EVPs induce cachexia, muscle wasting, coagulation and thrombosis, and neural reprogramming. These alterations contribute to the formation of a pre-metastatic niche (PMN) that facilitates cancer colonization and metastasis by recruiting bone marrow-derived cells (BMDCs) to modify the microenvironment, immune cells that suppress tumor immunity such as tumor-associated macrophages (TAMs) and regulatory T cells (Tregs), and neutrophils that promote metastasis. Dysregulation can also occur in T cells, dendritic cells (DC), and natural killer cells. Thus, the PMN becomes an immunosuppressed, metastasis-supporting environment. Once metastasis has taken place, the PMN transitions to a metastatic niche where angiogenesis, ECM remodeling, and progression of an immunosuppressive environment continue. In addition to directly modifying the microenvironment, tumor cells, stromal cells, and immune cells release EVPs that facilitate bidirectional communication/interaction. CAF: cancer-associated fibroblast.