Physiological impact of cell senescence in vivo: Tumour suppression

While the history of research on cell senescence counts for more than half a century, only in the last 10 years the functional relevance of cell senescence in vivo was established. The irreversible cell cycle arrest in OIS cells makes it an ideal mechanism to prevent tumour formation following oncogene activation, and in the first functional in vivo studies, cell senescence was established as a tumour suppressor mechanism.  OIS has been shown to be important for preventing lymphoma development and contribute to response to therapy. Using transgenic mice models to bypass the senescence response to oncogenic N-Ras resulted in the development of invasive T-cell lymphomas, whereas control mice only develop non-lymphoid neoplasia at a much later time point.     Another mouse model using inducible K-ras was used to make pre-malignant lesions that can develop into malignant tumours in lung and pancreas.  In these models,  biomarkers  of  cell  senescence  were  predominantly  identified  in  the  pre- malignant lesions but were lost once tumours developed.  To investigate OIS in vivo, a number of studies have focused on human nevi (moles), which are benign tumours of melanocytes that frequently harbor oncogenic mutations of BRAF.  The congenital nevi stained positive for markers of OIS, but not DNA damage in this instance.  BrafE600V, which is present in the nevi, induced p16(INK4a) expression in growth-arrested melanocytes both in vitro and in situ.  In contrast, another study in premalignant melanocytic lesions did show the presence of DNA damage foci, primarily located at telomeric regions as well as the p16(INK4a) expression.  In addition to activating mutations in oncogenes, cell senescence can be induced as a result of loss of tumor suppressor Pten in the prostate. Therefore, these combined studies clearly demonstrate that cell senescence acts as a potent tumor suppressor mechanism that prevents the development of multiple malignancies.

Link: Dominick G. A. Burton, Valery Krizhanovsky. Physiological and pathological consequences of cellular senescence. CMLS (2014)