FIGURE 1.

Metastatic colonization based on circulating tumor stem cells. Metastasis proceeds through multiple steps that occur in two major phases: (i) the pre-colonization phase of metastasis comprises physical translocation of cancer cells from the primary tumor to the circulation and (ii) the colonization phase after circulating tumor cell (CTC) extravasation. Cancer cells within the primary tumor undergo an epithelial-mesenchymal transition (EMT) process and endow invasive capacity, then intravasate into the tumor vasculature in the form of CTCs, which must be able to survive in the circulating blood and evade from the innate immune response and other defenses. Once CTCs home to a secondary site, the settlement in supportive niches enables them to survive and retain their stem-like tumor-initiating capacity. These cancer cells then enter a latent state lasting from months to decades while they adapt to their newfound microenvironment. When this latency is broken out, the cancer cells reinitiate overt outgrowth and overtake the local tissue microenvironment to commence the coming colonization.