Chromosomal anomaly seen as spurring colon cancer development

By Debbie Bolles / August 2011

In trying to decode what turns a normal human cell cancerous, UT Southwestern researchers have learned that chromosomal abnormalities may be among earliest factors that come into play.

Cancer-free cells taken from a patient’s colon were studied in a serum-free culture at UT Southwestern. Without manipulation, most of these cells developed an extra copy of one chromosome, called trisomy 7, an aberration also found in more than 40 percent of colorectal cancer cells. One factor in colon-cancer development is an abnormal number of chromosomes, called aneuploidy.

From left: Drs. Jerry Shay, Woodring Wright

“If we can figure out what causes aneuploidy, maybe we could develop a drug that would prevent normal chromosomes from becoming aneuploid,” said Dr. Jerry Shay, vice chairman of cell biology.

Dr. Shay, senior author of the study published in Neoplasia, said despite the surprising appearance of trisomy 7, the subsequent addition of four known cancer-causing variables did not evolve any of the cells toward cancer.

“Our data shows it isn’t so simple to take a normal cell and make it into a cancer cell; it takes a lot of different changes. We are now trying to figure out the right combination of changes to take this cell all the way to cancer so we can understand if there’s a way to intervene,” said Dr. Shay.

Just what caused these chromosomal changes in the cell cultures, researchers still don’t know. Perhaps stress or imperfect conditions in cell culture led to these cell changes. Why many cancer patients have chromosomal abnormalities also is unknown.

“It’s probably a combination of genetics and environment,” Dr. Shay said. “It doesn’t happen at birth, but usually in adults who have lived for a while.”

What’s also interesting, however, is that 20 percent of the colonic cells with trisomy 7 picked up another copy of a second chromosome, trisomy 20, when manipulated with other cancer-causing variables. Trisomy 20 is a chromosomal abnormality found in more than 85 percent of colon cancer cells.

“All those things together still didn’t cause cancer. Why? Probably because it takes seven or eight hits,” Dr. Shay said.

The next stage in Dr. Shay’s research will be to screen 8,000 small molecules and 1,500 natural products to see if any will kill off the abnormal trisomy 7 cells and keep regular, or diploid, cells alive. This study could lead to a potential new drug for patients at risk of colon cancer, such as those diagnosed with precancerous polyps, to prevent evolution of cells into cancer.

Other UT Southwestern researchers who participated in the NASA-supported study were lead author Peter Ly and Ugur Eskiocak, student research assistants in cell biology; Dr. San Bum Kim, postdoctoral researcher in cell biology; Dr. Andres Roig, assistant professor of internal medicine; Suzie Hight, student research assistant in the Nancy B. and Jake L. Hamon Center for Therapeutic Oncology Research; Kimberly Batten, research assistant in cell biology; and Dr. Woodring Wright, professor of cell biology. Researchers from Boston University School of Medicine assisted in the study.

Dr. Shay holds the Southland Financial Corporation Distinguished Chair in Geriatrics.

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