Molecular predictor of metastatic prostate cancer identified

LONDON - Researchers at Dana-Farber Cancer Institute have indicated that prostate tumors that carry a “signature” of four molecular markers have the potential to become dangerously metastatic if not treated aggressively.

The discovery lays the groundwork for the first gene-based test for determining whether a man’s prostate cancer is likely to remain dormant within the prostate gland, or spread lethally to other parts of the body.

By analyzing prostate cancer tissue from hundreds of men participating in a national health study, dozens of whom died of the disease, investigators led by Ronald DePinho, Lynda Chin and Zhihu Ding of Dana-Farber, in collaboration with Massimo Loda, of Dana-Farber and Brigham and Women’s Hospital, and Lorelei Mucci of Brigham and Women’s and Harvard School of Public Health, found that the four-gene/protein signature more accurately predicted which patients would die from metastatic spread than did the conventional method.

In the current study, researchers began with the well-established fact that prostate cancers without a working copy of the Pten gene tend to remain fairly idle and don’t trespass beyond the prostate gland itself. Researchers theorized that the loss of Pten in turn activates a collection of genes - a pathway - functioning to constrain the tumor’s growth and invasion. If that pathway was shut down, they reasoned, the tumor would begin to break loose from the prostate and spread insidiously through the body.

Using computational biology techniques to analyze gene activity in mouse prostate cancer cells with inactive Pten, the investigators found a few pathways that seemed to play a constraining role. One, known as TGF?-SMAD4 (for some of the genes that comprise it), was particularly intriguing as this pathway had been implicated in the metastasis of other tumor types in the past. When researchers conducted confirmatory molecular signaling studies to see what happens when Pten is knocked out of commission, signaling in the TGF?-SMAD4 pathway “shot through the roof,” DePinho says, suggesting that the pathway had sprung into action.

When researchers generated mice whose prostate cells lacked both Pten and the Smad4 gene, the animals developed large, fast-growing tumors that spread to their lymph nodes and beyond. Guided by these insights, they then examined whether something similar was happening in human prostate cancers.

Comparing the gene expression profiles of indolent versus aggressive mouse prostate cancers, they found about 300 genes that distinguished the two groups.

The researchers conducted an elaborate series of experiments to identify the genes most closely linked to the aggressive biology of prostate cancer. Among the hundreds of genes analyzed, two such genes stood out: SPP1 and CyclinD1, both of which, intriguingly, are close working partners of Smad4.

The four-gene signature - Pten, Smad4, SPP1, and CyclinD1 - showed its effectiveness as a predictive tool for survival when researchers drew on data from the Physicians’ Health Study, which has been tracking the health of thousands of U.S. physicians for nearly 30 years. When the investigators screened prostate cancer samples from study participants for the four-gene/protein signature, it was more accurate in predicting the ultimate course of the illness than conventional methods were.

“By integrating a variety of techniques - computational biology, genetically engineered model systems, molecular and cellular biology, and human tissue microarrays - we’ve identified a signature that has proven effective in distinguishing which men with prostate cancer are likely to progress and die from their disease and those who are not,” DePinho remarked.

The study has been published in the journal Nature. (ANI)