Investigators Enhance Irreversible Cell Growth Arrest to Prevent Tumors in Mice

A team of researchers has identified a new type of cellular senescence and determined a way to enhance it to suppress prostate tumor development and growth in mice. They believe that Pten-loss induced cellular senescence (PICS) is a viable approach to treating cancer.

The study is published online in The Journal of Clinical Investigation and is titled “A novel type of cellular senescence that can be enhanced in mouse models and human tumor xenografts to suppress prostate tumorigenesis.”

The work was led by Pier Paolo Pandolfi, Ph.D., of the Beth Israel Deaconess Medical Center. Dr. Pandolfi and his colleagues had previously determined that inactivation of the protein Pten leads to a senescence response that opposes tumorigenesis.

In his most recent study PICS was found to be advantageous over oncogene-induced senescence. Oncogene-induced senescence is thought to be invariably preceded by hyperproliferation, aberrant replication, and activation of a DNA damage checkpoint response (DDR), rendering therapeutic enhancement of this process unsuitable for cancer treatment.

Using mouse embryonic fibroblasts, Dr. Pandolfi’s group determined that PICS occurs rapidly after Pten inactivation in the absence of cellular proliferation and DDR. They also found that PICS is associated with enhanced p53 translation.

Additionally, the investigators were able to show that in mice p53-stabilizing drugs potentiated PICS and its tumor suppressive potential. Furthermore, they demonstrated that pharmacological inhibition of PTEN drives senescence and inhibits tumorigenesis in vivo in a human xenograft model of prostate cancer.

Taking their results together, they believe that PICS can be triggered in nonproliferating cells in the absence of DNA damage, which could be useful for developing a “pro-senescence” approach for cancer prevention and therapy.