Endostatin action and intracellular signaling: beta-catenin as a potential target?
Endostatin, the C-terminal part of collagen XVIII, has been shown to inhibit blood vessel formation in different pathological conditions characterized by increased angiogenesis, such as growing tumors. Subcutaneous injection of endostatin in tumor-bearing mice leads to decreased tumor growth, and even in some cases, cure of tumor disease. Endostatin has been tested in a clinical phase I study and shown not to be toxic. Whether the finding in mice that endostatin treatment does not result in development of resistance will hold true in humans is too early to tell. Endostatin binds to a specific motif in heparan sulfate, which may serve a co-receptor function. The structure of a potential primary receptor is not known. The mechanism of action of endostatin in inhibition of angiogenesis and thereby, inhibition of tumor growth, involves apoptosis of tumor cells. The most consistent effect of endostatin on endothelial cells in vitro is inhibition of endothelial cell migration, which may be due to disturbed cell-matrix interactions. An interesting candidate for transducing endostatin's effect on apoptosis and cell migration is beta-catenin, an intracellular protein which participates both in cell adhesion and in transcriptional regulation.
Dixelius
Johan
J
Department of Genetics and Pathology, Rudbeck Laboratory, Dag Hammarskjölds v. 20, 751 85 Uppsala, Sweden.
Cross
Michael J
MJ
Matsumoto
Taro
T
Claesson-Welsh
Lena
L
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D001172:Arthritis, Rheumatoid / Q000188:drug therapy; D003094:Collagen / Q000494:pharmacology*; D043170:Collagen Type XVIII; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D043169:Endostatins; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000098:blood supply; D010446:Peptide Fragments / Q000494:pharmacology*; D051381:Rats; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism*; D051176:beta Catenin
D020533:Angiogenesis Inhibitors; C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; D043170:Collagen Type XVIII; C495268:Ctnnb1 protein, rat; D003598:Cytoskeletal Proteins; D043169:Endostatins; D010446:Peptide Fragments; D015534:Trans-Activators; D051176:beta Catenin; D003094:Collagen