Figure 1.

The Sequential Process of Cancer Metastasis. Metastasis is a complex multi-step process. Tumor cells undergo remarkable morphological and phenotypical changes enabling migration and infiltration of adjacent sites as single cells or small clusters. An initial epithelial-to-mesenchymal transition (EMT) allows cells to acquire mesenchymal properties essential for motility and migration. Upon infiltrating local stroma, cancer cells intravasate into the vascular or lymphatic system and circulate throughout the body as circulating tumor cells (CTCs). In the circulation, disseminated CTCs must overcome barriers such as sheer-stress and the immune system. CTCs that survive the circulation extravasate and invade distant tissues by reestablishing characteristics of their corresponding primary tumor. CTC plasticity allows them to undergo the mesenchymal-to-epithelial transition (MET) to achieve this. Each step in this metastasis cascade is rate-limiting. Cells that successfully adapt to their microenvironment and resume proliferation successfully form overt secondary tumors. Alternately, cells that do not survive undergo cell death.