LOS ANGELES -- A gene that incites the development and growth of pituitary tumors is also expressed in colorectal tumors, pre-cancerous colorectal polyps, and, most abundantly, in invasive colorectal cancer, researchers at Cedars-Sinai Medical Center's Burns & Allen Research Institute report in this week's The Lancet. "The novel transforming gene known as Pituitary Tumor Transforming Gene (PTTG1) may prove to be a powerful tool for identifying colon polyps most at risk for becoming malignant and for distinguishing aggressive colorectal cancer, the third leading cause of cancer death in the U.S." said Anthony P. Heaney, M.D., lead author of the Lancet paper.
The discovery may lead to new therapeutic strategies as well, since PTTG1 appears to play an early and vital role in the sequence of events that converts normal cells to malignant ones, said senior author Shlomo Melmed, M.D., Director of Cedars-Sinai's Burns and Allen Research Institute and the Medical Center's senior vice president for Academic Affairs. "At the time of colonoscopy or colon cancer surgery, it could be determined whether cells express a high level of PTTG1. If so, that's a clear indication of neoplasia, so more aggressive therapy would be warranted," said Dr. Melmed. A gene that flashes an early warning of malignant activity may also prove useful in monitoring individual patient response to therapy designed to curb the spread of colon cancer.
Dr. Lin Pei and associates in Dr. Melmed's lab discovered PTTG1 in 1997, describing it as an oncogene that disrupts the normal steps of cell replication and activates a key player in tumor development called basic fibroblast growth factor, or bFGF. Once turned on, bFGF stimulates vessel growth to feed new tumors, ensuring their rapid growth and inexorable spread. PTTG1 can be found in low levels in most normal human tissues, but it is abundantly expressed in malignant cells and in pituitary tumors. Many different stages of cancer progression can be identified in colorectal cancer and Dr. Heaney theorized PTTG1 might be amplified in this disease and shed light on its role in this transformation process.
They examined samples from 68 colorectal tumors, including 48 carcinomas and 20 colonic polyps. PTTG1 was highly expressed in every carcinoma and 19 of 20 polyps. When a cancer had spread to a patient's nearby lymph nodes or liver, PTTG1 levels were significantly higher than if the cancer was confined to the bowel wall. Higher PTTG1 expression was also seen in tumors that were more vascular and therefore more primed to grow.
"These findings indicate that the novel transforming gene, PTTG1, may be a marker of invasive colorectal carcinoma," wrote Dr. Heaney.
Another important aspect of the discovery is that it will help scientists better understand the biology of tumor development. A key step in cancer research is unraveling the process by which normal cell growth is disrupted and abnormal cell proliferation begins. This gene seems to be a very early player in that process and acts early to sensitize the cell to other molecular events, driving the normal cell along a path towards cancer. Ironically, if Dr. Melmed's team had been studying colon cancer rather than pituitary tumors, the newly-discovered gene might have a different name. "This is how serendipity finds its way into science," he said. "We aren't oncologists, we aren't colon cancer scientists, we're endocrinologists who were looking at the pituitary when we found this gene. By chance, we were able to find it in other tumors as well."
This research was funded by the National Cancer Institute of the National Institutes of Health; the Doris Factor Molecular Endocrinology Laboratory at Cedars-Sinai, and by the Fulbright Association, which supports Dr. Heaney in the form of a Fulbright Scholarship.
Journal
The Lancet