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Genetic pathway may predict prostate cancer progression, metastasis
Ding Z. Nature. 2011;doi:10.1038/nature09677.
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A genetic pathway involving the transforming growth factor beta, bone morphogenetic protein and SMAD4 signaling axis may aid the Gleason score in predicting prostate cancer metastasis and fatality, according to recent study results.
Researchers from several sites in the US tested the hypothesis that pathways constraining progression may be activated in the prostate tumors of mice that were indolent (MOUSE)Pten-null. They aimed to determine whether the inactivation of progression barriers would lead to metastasis.
Robust activation of the transforming growth factor beta, bone morphogenetic protein (TGF-beta/BMP)–SMAD4 signaling axis was observed through comparative transcriptomic and canonical pathway comparisons of normal prostate epithelium and poorly progressive (MOUSE)Pten-null tumors. These findings were confirmed by biochemical analysis.
Invasive, metastatic and fatal prostate cancers with full penetration into the genetic deletion of (MOUSE)Smad4 in the (MOUSE)Pten-null mouse prostate confirmed the relevance of the SMAD4 axis in constraining tumors. Prostate cancer tumors without (MOUSE)Smad4/Pten model proliferated.
It was observed that cyclin D1 and SPP1 may be mediators of the biological processes of proliferation. Further analysis confirmed that cyclin D1 and SPP1 — along with PTEN and SMAD4 — “form a four-gene signature that is prognostic of prostate-specific antigen biochemical recurrence and lethal metastasis in human [prostate cancer],” the researchers wrote. “This model-informed progression analysis, together with genetic, functional and translational studies, establishes SMAD4 as a key regulator of [prostate cancer] progression in mice and humans.”
Once the pathway had been established as a potential marker, the researchers gathered data from the Physicians’ Health Study. They screened prostate cancer samples from participants with the four-gene model. The model enhanced the capacity of the Gleason score in predicting fatal outcomes among patients.
The researchers worked from the premise that prostate cancers that do not have a working copy of the PTEN gene do not progress beyond the prostate. They suggested that the conclusions drawn from the current analysis could lead to better clinical decisions and reduce unnecessary aggressive therapy. This could, in turn, improve quality of life and prevent the depletion of health care resources.
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