Inhibition of tumor angiogenesis by tumstatin: insights into signaling mechanisms and implications in cancer regression.
Growing tumors develop additional new blood vessels to meet the demand for adequate nutrients and oxygen, a process called angiogenesis. Cancer is a highly complex disease promoted by excess angiogenesis; interfering with this process poses for an attractive approach for controlling tumor growth. This hypothesis led to the identification of endogenous angiogenesis inhibitors generated from type IV collagen, a major component of vascular basement membrane (VBM). Type IV collagen and the angiogenesis inhibitors derived from it are involved in complex roles, than just the molecular construction of basement membranes. Protease degradation of collagens in VBM occurs in various physiological and pathological conditions and produces several peptides. Some of these peptides are occupied in the regulation of functions conflicting from those of their original integral molecules. Tumstatin (alpha3(IV)NC1), a proteolytic C-terminal non-collagenous (NC1) domain from type IV collagen alpha3 chain has been highlighted recently because of its potential role in anti-angiogenesis, however its biological actions are not limited to these processes. alpha3(IV)NC1 inhibits proliferation by promoting endothelial cell apoptosis and suppresses diverse tumor angiogenesis, thus making it a potential candidate for future cancer therapy. The present review surveys the physiological functions of type IV collagen and discovery of alpha3(IV)NC1 as an antiangiogenic protein with a comprehensive overview of the knowledge gained by us towards understanding its signaling mechanisms.
Sudhakar
Akulapalli
A
Cell Signaling and Tumor Angiogenesis Laboratory, Department of Genetics, Boys Town National Research Hospital, Omaha, NE 68131, USA. akulapallis@boystown.org
Boosani
Chandra S
CS
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D001324:Autoantigens / Q000494:pharmacology* / Q000627:therapeutic use; D024141:Collagen Type IV / Q000494:pharmacology* / Q000502:physiology / Q000627:therapeutic use; D006801:Humans; D039201:Integrin alpha3beta1 / Q000502:physiology; D039302:Integrin alphaVbeta3 / Q000502:physiology; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy*; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D015398:Signal Transduction / Q000502:physiology*
D020533:Angiogenesis Inhibitors; D001324:Autoantigens; D024141:Collagen Type IV; D039201:Integrin alpha3beta1; D039302:Integrin alphaVbeta3; C057112:type IV collagen alpha3 chain