Angiogenesis

Judah Folkman (1933-2008) pioneered the field of angiogenesis and its role in pathology, such as in cancer. Angiogenesis is a complex process of many steps. The zebrafish is a good model for analyzing the molecular basis of vasculogenesis and angiogenesis. Dorsal root ganglia (DRG) are a good example of the interactions of blood vessels and neurons.

Tumor Angiogenesis

Tumor cells attract blood vessels needed to deliver oxygen and nutrients, a prerequisite for tumor growth. Dr. Folkman suggested that cancer is an angiogenesis-dependent process.

Axon Guidance Angiogenesis

Both axons (via growth cones) and blood vessels (via EC tip cells) sense the environment for positive and negative cues, thus determining where they end up. At least four ligands and their receptors, first identified as mediators of axon guidance, have subsequently been found to regulate angiogenesis as well (Klagsbrun & Eichmann 2005).

Angiogenesis Inhibitors

A major goal in angiogenesis research has been to inhibit tumor angiogenesis and growth. One approach has been to block NRP expression. Both mouse knockouts and zebrafish knockdowns show that angiogenesis is NRP-dependent. NRP knockdown in zebrafish also affects motor neurons adversely. Because of the many steps involved in angiogenesis, there are numerous target possibilities. Blocking NRP expression is one approach; sequestering VEGF with a NRP B domain peptide is another. There are numerous other strategies for inhibiting tumor angiogenesis that are based on VEGF and NRPs. SEMA3F inhibits tumor growth and metastasis. One possible mechanism is that SEMA3F repels blood vessels and EC.

Tumor Endothelial Cells

Tumor blood vessels have abnormal morphology (McDonald, Nature Medicine 2003) and the EC are aneuploid with multiple chromosomes. The TRAMP model of spontaneous prostate carcinoma is useful for analyzing programmed tumor angiogenesis. TRAMP TEC are stem cell-like and can differentiate into cartilage and bone, concomitant with expression of cartilage- and bone-specific genes. Human prostate carcinoma blood vessels are calcified, indicative of bone formation in these hybrid cells.

Vascular Growth Factors

A number of vascular growth factors have been shown to affect the vasculature. Blood vessels are made up of endothelial cells (EC) and, in the case of larger blood vessels, smooth muscle cells as well. FGF and VEGF stimulate endothelial cell proliferation and migration. HB-EGF stimulates smooth muscle cell proliferation and migration. These vascular growth factors bind to heparin sulfate proteoglycans (HSPG), an important mediator of vascular growth factor activity.

FGF

Basic FGF was isolated and purified by Shing and Klagsbrun (Science 1984) as an EC mitogen and promoter of angiogenesis.

HB-EGF

HB-EGF was purified and cloned by Higashiyama and Klagsbrun (Science 1991). It is a transmembrane protein with many functions that is cleaved to release the soluble form of HB-EGF, an active mitogen.

VEGF

VEGF was purified by Ferrara and colleagues (1989). It is the major growth factor involved in physiological and pathological (cancer, retinopathy) angiogenesis. VEGF acts via three tyrosine kinase receptors and neuropilin (NRP). Different VEGF domains bind the various receptors.

Neuropilin 

Neuropilin 1 and 2 (NRP1, NRP2) bind both semaphorins (SEMA) and VEGF through their a1a2 and b1b2 extracellular domains, respectively. NRPs mediate axon guidance by forming complexes with plexins and mediate angiogenesis by forming complexes with VEGF receptor tyrosine kinases. Overexpression of NRP1 in tumor cells results in larger, more vascular tumors, probably via the VEGF/NRP1 pathway.