Schematic diagram of the metastatic process. (a) and (b) The growth and proliferation of tumor cells leads to hypoxia and regulate the enhanced release of VEGF, which further alters the properties of endothelial cells and promote the initiation of angiogenesis and lymphangiogenesis. (c) The higher permeability of the newly formed blood vessels and lymphatic capillaries drive an abnormal interstitial flow, and the increased stiffness of primary tumors leading to solid stressin vivo. Both factors promote the detachment of tumor cells from the primary site and penetration into the ECM. (d) Tumor cells migrate along the chemo-attractant, break the basement membrane, and enter the nearby blood vessel. Some of the tumor cells circulating in the vascular system adhere to the blood vessels of the local tissues and eventually form a secondary tumor.^[2,4,5]