Figure 1. The metastatic cascade -- from primary tumor to macrometastases.

Beginning with tumor initiating (stem) cells, a stepwise progression occurs from the tumors exiting the primary site of growth (local invasion and activation of metastatic phenotype) followed by systemic translocation (intravasation and transit through circulation) and finally adaptation and reawakening in distant metastatic sites (extravasation, micrometastases formation and colonization leading to clinically detectable active macrometastases). The metastatic process requires activation of cancer stem cells and interaction with surrounding stromal cells throughout the program.