Chen Z et al. (2005) Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis. Nature 436: 725–730

Researchers at Memorial Sloan–Kettering Cancer Center have discovered that induction of CELLULAR SENESCENCE slows the development of prostate cancer in mice. The team also found evidence of senescence in human prostate tumors, demonstrating the therapeutic relevance of their findings.

Chen and colleagues engineered mice in which the tumor-suppressor genes Pten and/or Trp53 (encoding the p53 protein) were inactivated in the prostate after puberty. Histopathologic analysis revealed that mice with an inactivated Pten gene developed high-grade PROSTATIC INTRAEPITHELIAL NEOPLASIA, which eventually developed into nonlethal prostate cancer, whereas those with an inactivated Trp53 gene had healthy prostates. However, mice with both Pten and Trp53 inactivated rapidly developed invasive prostate cancer and died within 7 months. From these observations, the authors postulated that loss of Trp53 accelerates the progression of prostate cancers initiated by inactivation of Pten.

The researchers used mouse embryonic fibroblasts to explore the molecular basis of their observations, and found that acute homozygous loss of Pten arrests growth in prostate cancer cells via the p53-dependent cellular senescence pathway.

Immunohistochemical analysis of samples from 12 early-stage human prostate tumors showed strong staining for senescence in regions where premalignant changes were seen, but rarely in carcinomatous regions, providing further evidence that loss of p53 function is associated with prostate cancer progression.

In light of their findings, the authors suggest that drugs that potentiate activation of p53 could be developed to induce cellular senescence in PTEN-deficient prostate cancer, thus slowing its progression.