Regulation of nitric oxide signaling by thrombospondin-1: implications for anti-angiogenic therapies

The current US Food and Drug Administration (FDA)-approved angiogenesis inhibitors for cancer therapy block vascular endothelial growth factor (VEGF) binding to the VEGF receptor (VEGFR2) (the inhibitor bevacizumab) or inhibit the tyrosine kinase activity of VEGFR2 (the inhibitors sorafenib and sunitinib). VEGFR2 activates several parallel signaling pathways that control angiogenesis, but inhibiting NO/cGMP signaling blocks most of these responses. Therapeutic responses to VEGF inhibitors may be limited by parallel activation of the downstream pathways by additional angiogenic factors produced by tumors that can activate NO/cGMP signaling independent of the VEGF receptor such as adrenomedullin, angiopoietin-1, sphingosine 1-phosphate (S1P), lysophosphatidic acid (LPA), angiopoietin-related growth factor (AGF), estrogens, insulin, and fibroblast growth factor-2 (FGF2), –. Therefore, inhibitors that act on essential downstream pathways may be more effective than the existing VEGF/VEGFR antagonists for controlling tumor angiogenesis. Endostatin is one such agent that acts via the phosphatase PP2A to inhibit nitric oxide synthase (eNOS) activation and downstream to inhibit soluble guanylate cyclase (sGC) expression. Thrombospondin 1 (TSP1) is a redundant inhibitor of the NO/cGMP cascade, and the experimental drug ABT-510, a TSP1 mimetic, inhibits angiogenesis via the TSP1 receptor CD36. However, native TSP1 also acts through the more potent inhibitory pathway mediated by CD47. Proangiogenic factors and signaling pathways are shown in green, and anti-angiogenic factors and pathways are in red.

Publication

Regulation of nitric oxide signaling by thrombospondin-1: implications for anti-angiogenic therapies. () Jeff S. Isenberg, et al. Nat Rev Cancer. ;9(3):182-194. Figure: F4. All organisms Homo sapiens Mus musculus Rattus norvegicus Drosophila melanogaster

Disease mentions