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Mouse Studies Point to Prognostic Test for Prostate Cancer

Some mice, like some men, develop prostate cancer that never spreads beyond the prostate, and researchers have used these mice to learn why only some tumors metastasize and become fatal. By studying genetically engineered mice, the researchers identified four genes that drive the progression of prostate tumors. The corresponding genes in humans also appear to influence the spread of prostate cancer and could become prognostic markers for identifying potentially lethal tumors in patients, the researchers reported online in Nature on February 2.

New tests are needed to distinguish lethal prostate tumors from those that would never cause harm in a man’s lifetime. But, given the enormous intratumoral heterogeneity of human prostate cancers, Dr. Ronald DePinho of the Belfer Institute for Applied Cancer Science at Dana-Farber Cancer Institute and his colleagues decided to look for prognostic markers in genetically engineered mice, which are more amenable to genetic analysis. Using unbiased approaches, the investigators discovered that a mouse gene called Smad4 constrains the spread of tumor cells.

Additional experiments and lines of evidence, including functional studies and cross-species comparisons of genes, implicated four genes, including Smad4, in the progression of prostate cancer in mice. The researchers concluded that the process is governed largely by the inactivation of the genes Smad4 and Pten and activation of two other genes, cyclinD1 and Spp1.

They next assessed the prognostic value of the corresponding genes in human prostate cancer, using the protein products of the genes as markers. When added to standard clinical parameters such as the Gleason score, the researchers found these markers improved predictions of death from metastatic prostate cancer among men who participated in the Physicians’ Health Study and in a second study.

“We used the mouse models to filter out the intractable genomic complexity that presents itself in early-stage human cancers,” said Dr. DePinho. “And this allowed us to identify a collection of markers that are functionally relevant to the biology of invasion.” A company has licensed the four markers for further development, he added.

Source: NCI Cancer Bulletin