Researchers identify cellular mechanism that arrests PCa

Researchers at Memorial Sloan-Kettering Cancer Center, New York, have determined that prostate tumor growth is arrested through a biological process called cellular senescence, in which cells stop proliferating and remain alive but fail to respond to normal growth signals. This research provides some of the first evidence that this phenomenon, normally associated with stress and/or aging, also occurs in cancer both in animal models and in humans (Nature 2005; 436:725-30).

Prostate cancer is caused by changes in several tumor suppressor genes including PTEN and p53. The researchers suggest that drugs that support p53 function could delay progression of prostate cancer in PTEN-deficient prostate cancer by triggering cellular senescence.

"In attempting to clarify the role of the PTEN and p53 tumor suppressor genes in advanced prostate cancer cells, we unexpectedly discovered that acute loss of PTEN results in increased, not decreased, p53 function. This works to suppress the further development of cancer," said senior author Pier Paolo Pandolfi, MD, PhD. "If we can maintain a higher level of p53 in prostate cancer and induce cellular senescence, the disease should remain stable. This provides new opportunities for therapeutic intervention."

To determine whether their findings were relevant to human prostate cancer, the researchers performed immunohistochemical analysis of prostate tissues. They detected a marker for activation of the senescence pathway when PTEN was inactivated. Next, they examined early-stage human prostate cancer sections stained for the senescence marker under high magnification. The senescence marker was seen in areas of hyperplasia that may precede the development of carcinoma.

"We are working to use these models to design more effective clinical tests by determining which combination of agents is most likely to be effective," said Howard Scher, MD, a co-author. "We are already testing specific drugs to restore PTEN function, based on its role in prostate cancer development and progression."