Tumor Growth Requires Formation of New Blood Vessels

Tumors must recruit new blood vessels in order to grow to a large size. In the absence of a blood supply, a tumor can grow into a mass of about 10⁶ cells, roughly a sphere 2 mm in diameter. At this point, division of cells on the outside of the tumor mass is balanced by death of cells in the center from an inadequate supply of nutrients. Such tumors, unless they secrete hormones, cause few problems. However, most tumors induce the formation of new blood vessels that invade the tumor and nourish it, a process called angiogenesis. This complex process requires several discrete steps: degradation of the basement membrane that surrounds a nearby capillary, migration of endothelial cells lining the capillary into the tumor, division of these endothelial cells, and formation of a new basement membrane around the newly elongated capillary.

Many tumors produce growth factors that stimulate angiogenesis; other tumors somehow induce surrounding normal cells to synthesize and secrete such factors. Basic fibroblast growth factor (β-FGF), transforming growth factor α (TGF-α), and vascular endothelial growth factor (VEGF), which are secreted by many tumors, all have angiogenic properties. New blood vessels allow the tumor to increase in size and thus increase the probability that additional harmful mutations will occur. The presence of an adjacent blood vessel also facilitates the process of metastasis.

The VEGF receptors, which are tyrosine kinases, regulate several aspects of blood vessel growth, such as endothelial cell survival and growth, endothelial cell migration, and vessel wall permeability. VEGF expression can be induced by oncogenes and by hypoxia, defined as a partial pressure of oxygen of less than 7 mmHg. The hypoxia signal is mediated by hypoxia-inducible factor 1 (HIF-1), a transcription factor that is activated in low-oxygen conditions and which binds to and induces transcription of the VEGF gene and about 30 other genes, many of which can affect the probability of tumor growth. HIF-1 activity is controlled by an oxygen sensor composed of a prolyl hydroxylase that is active at normal O₂ levels but inactive when deprived of O₂. Hydroxylation of HIF-1 causes ubiquitinylation and degradation of the transcription factor, a process that is blocked when O₂ is low. Compounds that inhibit angiogenesis have excited much interest as potential therapeutic agents, but their success in the clinic has thus far been limited.