A study led by researchers at The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute has found that the normal cells in tumors, known collectively as the tumor stroma, may lose more regions of DNA than do the cancer cells in the course of tumor development.
When DNA is lost, the genes located in those regions are also lost. "Cancer geneticists have looked upon the stroma as just innocent soil that passively receives the seed in which cancer grows," says Charis Eng, the Dorothy E. Klotz Chair of Cancer Research and director of the clinical cancer genetics program.
"But our study indicates that genetic damage occurs in stromal tumors cells, and that that damage may play an important role in tumor development."
The findings might help explain why tumors often behave differently, and respond differently to treatment, in people with seemingly identical cancers. The genetic changes in stromal cells also may provide new targets for future anti-cancer drugs and present a new strategy for treating and preventing cancer, says Eng, a recipient of the Doris Duke Distinguished Clinical Scientist Award.
The study is published in the Oct. 15 issue of the journal Cancer Research.
How the DNA damage occurs in stromal cells isn't yet known, but it might result from exposure to carcinogens, Eng says. It's also too soon to say how genetic damage to stromal cells might influence tumor growth.
However, stromal cells can produce growth factors and other substances that can influence the behavior of cancer cells. The loss of chromosome regions may result in the loss of genes that control these substances. Stromal cells may also produce factors that limit the growth of nearby cells. Loss of genes for such factors would remove those inhibitors and allow cancer cells to grow.
"But those are only hypotheses," Eng says. "I think that the stroma plays an important role in enabling a tumor to invade neighboring tissue and spread. If that proves to be true, someone may someday develop a drug that targets stroma cells and prevents the cancer from spreading."
Eng and her colleagues analyzed 134 tissue samples from invasive breast tumors. They examined stromal cells known as fibroblasts, the major component of the tumor stroma. Fibroblasts produce the fibrous scaffolding in tumors and normal tissues. (Stromal cells also include immune cells, fat cells and blood vessel cells.)
The investigators used 381 molecular markers scattered throughout the human genome (the entire set of human chromosomes). The markers served as signposts that identify various regions of the 46 human chromosomes.
Among the fibroblasts, the researchers found that 38 markers – or 38 regions of DNA – were lost from 19 different chromosomes. When the researchers then looked for the markers in the cancer cells, they found that 19 regions of DNA were lost from 15 different chromosomes.
This indicates that more DNA regions may be lost in a tumor's stromal cells than in its cancer cells. Furthermore, the losses were not spread randomly over the chromosomes. Instead, they were clustered in specific regions, or hotspots, on chromosomes, suggesting that they may play a role in tumor development.
The researchers are now looking for correlations between the stromal genetic damage seen in patients' tumors and how those tumors behave and respond to therapy.
Other OSU researchers involved in this study were Koichi Fukino, a postdoctoral researcher; Lei Shen, assistant professor in the School of Public Health; Satoshi Matsumoto, postdoctoral researcher; and Carl D. Morrison, assistant professor of pathology.
Source: Eurekalert & othersLast reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
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