The metastatic cascade. Tumor cells that acquired an invasive phenotype detach from the primary lesion, invade the surrounding tissues and move toward neighboring blood vessels. Then tumor cells intravasate into the blood circulation are carried by the flow, usually until they arrest by size restriction in small capillaries at the distant site. In the following step, tumor cells exit the circulation and invade the foreign microenvironment. In a secondary site, tumor cells can exist as small pre-angiogenic micrometastases, solitary dormant tumor cells or dormant micrometastatic lesions. To develop into an active macrometastatic lesion, the tumor cells must evade destruction by host defense mechanisms, adapt to the new microenvironment, initiate proliferation and create vascular network. Very few extravasated tumor cells are able to accomplish these tasks, and the majority of them undergo apoptosis.