UIC Researchers Pinpoint Genes Involved In Cancer Growth

Some of these genes appear to be linked with the growth of cancerous cells only -- not healthy cells -- making them possible targets for new drugs that could halt the spread of disease without necessarily compromising normal processes.

Results of the study appear in the July 22 issue of Cancer Cell.

The research relied on a strategy pioneered in the laboratory of Igor Roninson, distinguished professor of molecular genetics in the UIC College of Medicine. The strategy involves cutting human DNA into tiny, random fragments, inserting the fragments into a mammalian cell using a vector, or delivery vehicle, and inducing them to express their genetic information.

Some of the fragments prove to be biologically active by interfering with the function of the genes from which they are derived.

In the new study, certain fragments inhibited the multiplication of breast cancer cells by shutting down the genes necessary for cell growth. The experiment enabled researchers in Roninson's laboratory, led by research assistant professor Thomas Primiano, to locate 57 genes involved in cell proliferation.

They identified the genes by matching the growth-inhibiting fragments with sequences in the human genome.

"Our strategy was validated by the fact that more than half of the genes we identified were already known to play key roles in the growth of cells or the development of cancers," Roninson said. "Many of the other genes, however, were not previously known to be involved in cell division and proliferation. In fact, the functions of some of these genes were entirely unknown."

Analysis of animal studies conducted by other investigators allowed Roninson's group to determine which genes were likely involved in the growth of tumor cells but not normal cells. In so-called "knockout" mice, 20 of the genes the scientists identified as essential for the growth of breast cancer cells had previously been disabled.

Lacking any of six of these genes, the animals died in utero. But mice missing any of the other 14 genes matured to adulthood, suffering only limited problems in specific organs.

"Obviously, the best drug targets would be genes that are needed only by cancer cells," Roninson said.

One of the genes the UIC researchers identified manufactures a protein found on the cell surface called L1-CAM, which is involved in the development of the nervous system and was not previously known to play a role in cancer cell growth.

Using antibodies to L1-CAM to disturb its function, the researchers stopped the growth of breast, colon and cervical cancer cells in a petri dish, but left unimpaired the growth of normal breast tissue cells and fibroblasts, which make up connective tissue.

This final experiment, Roninson said, confirmed the value of his team's study.

"One of the main reasons for sequencing the human genome was the hope that this knowledge would help scientists find molecular targets for new and better medicines," Roninson said. "The genes we have identified clearly have the potential to serve as targets for novel therapeutics in the fight against cancer."

Other UIC researchers involved in the study were Mirza Baig, Anil Maliyekkel, Bey-Dih Chang, Stacey Fellars and Justin Sadhu. The UIC team collaborated with scientists Sergey Axenovich and Tatyana Holzmayer at PPD Discovery, Inc.

PPD Discovery, Inc. and the National Institutes of Health funded the study.

For more information about the UIC College of Medicine, visit http://www.uic.edu/depts/mcam/.