The angiogenic role of interleukin-8 in lung cancer
Creators: name: University Of California Office Of The President
Publisher: name: University of California Office of the President
publisherIdentifier: https://ror.org/00dmfq477
publisherIdentifierScheme: ROR
Year: 2024

description: Smoking increases the risk for lung cancer considerably, and the fear of lung cancer is of great concern to all whom have smoked. In spite of advancement in the understanding and treatment of lung cancer, the long-term prognosis of lung cancer still remains poor, primarily because many lung carcinomas seed metastases before they are diagnosed. Since metastatic microtumors of the lung are particularly resistant to current therapies, novel strategies for their treatment are necessary. One promising novel strategy is to target the blood supply of the tumor. 
 
 
 
 
 
 This project seeks to block critical factors in the growth of new blood vessels (angiogenesis) into the tumor. Both primary and metastatic lung cancer cells depend on an external blood supply for their survival, but while the primary tumor can be resected, this is not true for all the metastases that have spread out from it. Since angiogenesis is so important for the development of both the primary tumor and of all metastases spreading out from it, lung carcinomas produce various angiogenic factors that signal to the endothelial cells that line the blood vessels to migrate towards the tumor cells and sprout new microvessels surrounding the tumor. If this step could be inhibited, metastases could be prevented and the life of many long-time smokers prolonged. 
 
 
 
 
 
 Although it is known that lung cancer cells produce interleukin-8 (IL-8), and that IL-8 is angiogenic in vivo, it has found littleattention in lung cancer research. Interleukin-8 is better known for its role in inflammatory diseases, where it attracts white blood cells into an area of tissue injury. White blood cells express two kinds of interleukin-8 receptors, called CXCR1, which mediates white cell migration, and CXCR2, whose function is poorly understood. Because of experimental difficulties in detecting IL-8 on endothelial cells, it had been assumed that these receptors are lost in culture. Using a method that shows functional changes of the cytoskeleton (the cellular machinery for cell movement), we have recently shown that lung-derived endothelial cells in culture respond to IL-8, that the CXCR1 is activated briefly and the CXCR2 for prolonged periods of time. This opens the possibility to study the molecular mechanisms involved in the endothelial cell response in several in vitro angiogenesis assays, which include cytoskeletal rearrangement, cell migration and sprouting of vessel-like structures in response to IL-8 or to IL-8 containing supernatants of lung cancer cells. Several approaches will then be taken to prevent these responses. These include blocking antibodies to either of the two receptors and inhibitors that interfere with the IL-8 signal transduction cascade, which is not identical for the two receptors. If the angiogenic response of IL-8 on endothelial cells is due to activation of the CXCR2, as suggested by preliminary results, it appears possible to block this effect of IL-8, mediated by the CXCR2 without interfering with the immune protective role of the CXCR1 on white blood cells. While definition of the molecular mechanisms involved in IL-8 mediated angiogenesis is the immediate goal of this project, potent inhibitors of this angiogenic response are likely to be developed into therapeutics, which will hopefully eradicate metastatic lung cancer in the future.