Molecular BIology of Cancer Topics
Angiogenic factors stimulate vascular endothelial cell growth, invasiveness, migration and differentiation. Such factors include fibroblast growth factors (FGFs), vascular endothelial growth factors (VEGFs), angiogenin, transforming growth factors alpha and beta (TGFa and TGFb), tumor necrosis factor alpha (TNFa), platelet-derived endothelial growth factor (P-EGF), granulocyte colony stimulating growth factor, placental growth factor, interleukin 8, and hepatocyte growth factor. The two most important angiogenic factors are basic fibroblast growth factor (bFGF) and VEGF.
There are two kinds of FGFs: basic (bFGF) and acidic (aFGF). bFGF and its receptors are ubiquitously expressed.
Angiogenesis is regulated by the balance between activators and inhibitors. Activators of angiogenesis include aFGF, bFGF, VEGFs and others. Inhibitors include thrombospondin-1, 16 kd prolactin, interferon b/g, platelet factor 4, endostatin, angiostatin and others.
Endostatin inhibits growth of capillary endothelial cells but not other cell types. It also inhibits tumor growth in vivo. Treatment of cancer-bearing mice with endostatin causes tumor cell death by increasinh apoptosis and inhibits tumor growth by 99% (20 mg/kg/day).
VEGF
VEGF receptors are expressed only in vascular endothelium. There are two principal VEGF receptors: Flt (VEFGR-1) and Flk (VEGFR-2/KDR). Other VEGF receptors are Flt-4 (VEGFR-3) anf NRP-1. Different forms of VEGF will defferentially bind some receptors but not others. VEGF-A activates both Flt-1 and Flk-1, while VEGF-B activated Flt-1 but not Flk-1. VEGF-C, VEGF-D nd VEGF-E activate Flk-1 but not Flt-1. In hypoxic areas of the tumor, VEGF is induced and stimulates angiogenesis.
VEGF expression is associated with poor prognosis inmany cancers. In lung cancer patients, low VEGF levels are associatred with a median survival of 151 months, while high levels are associated with a median survival of only 8 months.
At least two therapeutic agents are in development tht target VEGF receptors: SU5416 and bevacizumab. SU5416 (semaxamib) inhibits Flt-1 by competing with ATP, thus inhibiting the receptor's tyrosine kinase activity. Bevacizumab is a monoclonal antibody inhibitor of VEGFR-2. As of 2004, SU5416 is in early clinacal trials. Bevacizumab is in phase II clinical trials for colon cancer and so far is able to icrease respose from 15% to 40% if added to chemotherapy at a low dose.
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