Common cancer gene controls blood vessel growth

Scientists from the Kimmel Cancer Center at Johns Hopkins and Northwestern University have found a new target to squeeze off a tumor’s blood supply. Research published in the December 17 issue of Cancer Cell shows how a common cancer-causing gene controls the switch for tumor blood vessel growth known as angiogenesis.

Recent evidence has shown that this gene, called Id1, is important for angiogenesis, a factor in cancer progression because it provides a needed blood source to tumor cells.

The new study concludes that the Id1 gene controls the angiogenesis pathway in certain cancers by turning off the production of a protein, thrombospondin-1 (TSP-1), a naturally occurring angiogenesis suppressor.

“We found activation of the Id1 gene, which is highly expressed in melanoma, breast, head and neck, brain, cervical, prostate, pancreatic and testicular cancers, results in decreased expression of TSP-1 and increased tumor blood vessel formation,” says Rhoda M. Alani, M.D., assistant professor of oncology, dermatology, molecular biology and genetics in the Kimmel Cancer Center at Johns Hopkins and director of this study.

The researchers also found TSP-1 levels that were three- to fivefold greater in mice with Id1 gene function turned off than in mice with normal Id1.

To confirm their findings, the research team monitored blood vessel growth in mice with normal and crippled Id1 genes, then added a chemical that wiped out TSP-1. Control mice with normal Id1 showed well-developed blood vessels. Mice with a non-functioning Id1 gene showed little blood vessel growth when TSP-1 was activated. When the anti-TSP chemical was added to these mice, blood vessel growth resumed.

Efforts to find a way to use TSP-1 as an anti-cancer agent are under way in animal studies. “Because TSP-1 occurs naturally throughout the body, it can’t be used as a drug,” says Roberto Pili, M.D., assistant professor of oncology in the Kimmel Cancer Center and co-author of the study. “But it could potentially be paired with another molecule and programmed to be released only in tumors.” In addition to TSP-1, Alani and colleagues are studying Id1 targets important in other biologic processes, including signaling pathways inside cells.

This research was funded by the National Institutes of Health and the American Cancer Society.

Co-authors include Olga Volpert at the RH Lurie Cancer Center at Northwestern University, Hashmat Sikder at Johns Hopkins, Thomas Nelius and Tetiana Zaichuk from Northwestern, and Chad Morris, Clinton Shiflett, Meghann Devlin and Katherine Conant at Johns Hopkins.

Volpert, Olga V. et al, “Id1 regulates angiogenesis through transcriptional repression of thrombospondin-1,” Cancer Cell, Dec. 2002, Vol. 2.