Cellular Senescence - its role in cancer and the response to ionizing radiation

Cellular senescence is a metabolically active form of irreversible growth arrest that halts the proliferation of ageing and/or damaged cells and as a consequence, prevents the transmission of damage to daughter cells. This complicated cellular event is initiated in response to a variety of intrinsic and extrinsic genotoxic stimuli [1-4] and mediated through tumour suppressor pathways involving p53, and p16INK4A/pRb [5,6]. This ultimately leads to the inhibition of cyclin-dependant kinases [7,8]. Accordingly, cellular senescence can be thought of as a tumour suppressor mechanism. Indeed the majority of cancers have mutations in p53 and/or the pRb/p16 pathways, while germ-line mutations in these pathways result in a cell-specific ability to overcome senescence-inducing signals, thereby greatly increasing their susceptibility to cellular transformation [9-11]. The importance of cellular senescence as a tumour suppressor is further demonstrated by cell fusion experiments [12] that provide evidence that growth arrest observed in senescent cells has a strong influence over the growth in proliferating cells and cellular oncogenes of tumour cells. When proliferating cells were fused with senescent cells, DNA replication was inhibited even in the presence of mitogens, and when senescent cells were fused with tumour cells, DNA replication was similarly inhibited. These fusion experiments led to the assumption that senescent cells contained control elements capable of exerting a dominant effect over proliferating pre-senescent cells. Importantly, this tumour suppressive mechanism of cellular senescence has been supported in both mice and human studies [13].As well as possessing tumour suppressive mechanisms, senescence has been found to play an important role in wound healing and tissue repair and/or communication to surrounding tissues/cells of damage crisis to assist healing [14,15]. For instance, senescent cells have been shown in in vivo mouse models to play a role in the