Figure 3.

Blood vessels drive macrometastatic tumor growth and secondary colonization. Through still unknown mechanisms, tumor cell proliferation is stimulated and outpaces apoptosis (P>A) in the micrometastatic tumor. This progression is possible when blood vessel ingrowth is promoted (that is, angiogenic switch). A major driver of this process is the production of angiogenic growth factors by the hypoxic tumor cells, resulting from activation of hypoxia-inducible factor (HIF) signaling. In addition to HIF-dependent stimulation of angiogenesis, tumor cell intrinsic signaling increases the production of angiogenic growth factors, further enhancing metastatic outgrowth and secondary metastasis to distant organs.