The researchers discovered that the gene, called 15-PGDH, is found in normal cells and is virtually undetectable in colon cancer cells. When the researchers restored the gene in tumor cells and injected them into immune-deficient mice, the mice showed little or no tumor development. The study appears in the Dec. 14 issue of the Proceedings of the National Academy of Sciences.
The gene 15-PGDH acts as an antagonist to control an enzyme called COX-2. An increase in COX-2 is a major early event in the genesis of human colon tumors.
Sanford Markowitz, M.D., the Francis Wragg Ingalls Professor of Cancer Genetics at Case and UHC and senior author of the paper, said, "This gene may represent the first of a one-two punch in colon cancer. In colon cancers a dramatic increase of COX-2 is seen. 15-PGDH would act to antagonize and check this increased COX-2 activity. Without 15-PGDH present,unchecked COX-2 goes on to cause abnormal changes on the cellular level, which may lead to tumor development."
Previous studies have shown that patients who take nonsteroidal anti-inflammatory drugs (NSAIDs), which are COX-2 inhibitors, have a lower incidence of colon cancer. COX-2 inhibitors have been shown to shrink the size of tumors in mice. Markowitz likens the 15-PGDH gene to a naturally occurring COX-2 inhibitor. (Celebrex, a popular arthritis drug, is also a COX-2 inhibitor.)
Markowitz found that 15-PGDH is directly controlled and activated by another gene, called TGF-beta. Normally, TGF-beta sends a signal that allows the colon to shed cells weekly as a way of helping to block development of colon cancers. In 1995, Markowitz discovered colon cancers have mutations that inactivate the TGF-beta pathway.
"If there is no TGF-beta signal, there is no 15-PGDH. That means the opponent to COX-2 is gone, and the COX-2 oncogene activity is unopposed," said Markowitz. "This interaction between TGF-beta and 15-PGDH points to the importance of the TGF-beta system in suppressing colon cancer. These genes give us targets that we can aim for in the development of new drugs or gene therapies that may help us treat or prevent colon cancer," said Markowitz, who is also an investigator with the Howard Hughes Medical Institute.
Lead authors on the paper are Min Yan of the departments of medicine, molecular and microbiology at Case Western Reserve University School of Medicine and the Ireland Cancer Center at University Hospitals of Cleveland, and Ronald M. Rerko of Howard Hughes Medical Institute. Also involved were researchers from the University of Kentucky and the Protein Design Laboratories in Freemont, Calif.