December 31, 2010
Ovarian Cancer Progresses When Genes are Silenced
(Ivanhoe Newswire) "“ Many mechanisms change the activity of genes. Epigenetics determine when genes are turned on and off, and these epigenetics allow for cells to become cancerous. This was especially seen in ovarian cancer.
Researchers at the Duke Cancer Institute have found evidence of epigenetics at work on a genome-wide scale in cases of ovarian cancer. One major biological signaling pathway in particular was found to contain many genes influenced by DNA methylation, a mechanism for turning off genes, in tumor cells.
The researchers conducted a series of studies on cancer cell lines and primary tumor specimens from ovarian cancer patients by comparing the genome-wide gene expression profiles of cells that were treated or mock-treated with drugs that inhibit DNA methylation. They identified 378 candidate methylated genes, and from these all 43 of the predicted genes the researchers analyzed showed methylation in ovarian cancers.
"We were very surprised to see that so many of these genes were part of one pathway, the TGF-beta signaling pathway, so we conducted studies to further explore how methylation might have an effect on the pathway," senior author Susan Murphy, Ph.D., assistant professor in the Division of Gynecologic Oncology in Duke OB-GYN and in the Department of Pathology, was quoted as saying.
When the researchers treated tumor cells with methylation inhibitors, the TGF-beta pathway showed increased activity. This is an important signaling pathway that directs many processes in cells. A perfectly functioning TGF-beta pathway ensures proper cell growth, cell differentiation, and apoptosis (programmed cell death), and helps prevent tumor formation. When this pathway isn't regulated, it can instead help tumors grow and metastasize.
The study showed for the first time that TGF-beta pathway function is regulated through methylation. "This is only one piece of a larger puzzle about the biology of ovarian cancer, but we can say that DNA methylation does have an influence on suppressing TGF-beta pathway signaling, which contributes to ovarian cancer." Murphy explained.
In addition, the genes they studied included a cluster of genes that strongly correlated with TGF-beta pathway activity in specimens from older women, which suggested that age-related epigenetic changes can accumulate and may contribute to cancer.
Murphy said two different groups of patients the team identified might need different approaches.
"Some women with ovarian cancer have lower expression of these tumor-suppressing genes and may be amenable to epigenetic therapies that lead to gene reactivation "“ with the caveat that at this point we can't epigenetically reactivate just one gene or a specific group of genes," Murphy said. "Another group of women with ovarian cancer have higher expression of these genes, suggesting it may be possible to specifically inhibit particular components in this pathway to stop tumor development or progression."
SOURCE: Genome Research, published online December 30, 2010