Figure 1.

Hematogenous metastatic route. The metastatic cascade starts with molecular and morphological changes in cancer cells, enabling their release from the primary tumor. The production of tumor secreted factors (e.g. MMPs) by cancer cells to degrade the extracellular matrix (ECM) (1), helps the gain of migratory and invasive abilities (2). The metastasizing cancer cells, depending on the cancer type, rely on epithelial to mesenchymal transition (EMT), in which cancer cells acquires a mesenchymal phenotype through the loss epithelial cell-cell contacts, as E-Cadherin, to facilitate the penetration into the basal membrane. However, in other scenarios collective or cluster‐based migration and invasion can contribute to cancer cell intravasation independent of EMT. The different phases of the hematogenous metastatic cascade are: local invasion (1 and 2); intravasation into vessels (3); circulation into the bloodstream (4); extravasion into a distant organ or tissue (5), and the formation of a secondary tumor in the metastatic niche (6). The metabolic remodeling during the metastatic processes is crucial for the efficient colonization of cancer cells in distant sites, typically nutrient and oxygen-rich areas, as lungs, liver, bones and brain.