Fig. 2.

CSC-derived exosomes regulate the initial invasion and metastasis site of cancer cells. Establishment of distant metastasis may partially result from exosome-carried signals shared between adjacent cells and long-distance cells in the body. Step 1, invasion and intravasation: cancer cells in situ break through basement membrane with the infiltration of immune cells and enter the blood vessel through the endothelial cells. Exosomes regulate the surrounding cells to promote EMT and metastasis. Step 2, circulation: exosomes and cancer cells transport to the distant site with blood fluid. Step 3, extravasation: exosomes and cancer cells enter interstitial through the endothelial cells. Exosomes bind to specific tumor microenvironmental cytokines and are taken up in specific tissues, forming a pre-metastatic niche, which can recruit CSCs and cancer cells to reside. Step 4, colonization: exosomes and cancer cells colonize distant target organs to further facilitate neoplastic growth