Senescence induction; a possible cancer therapy

Abstract

Cellular immortalization is a crucial step during the development of human cancer. Primary mammalian cells reach replicative exhaustion after several passages in vitro, a process called replicative senescence. During such a state of permanent growth arrest, senescent cells are refractory to physiological proliferation stimuli: they have altered cell morphology and gene expression patterns, although they remain viable with preserved metabolic activity. Interestingly, senescent cells have also been detected in vivo in human tumors, particularly in benign lesions. Senescence is a mechanism that limits cellular lifespan and constitutes a barrier against cellular immortalization. During immortalization, cells acquire genetic alterations that override senescence. Tumor suppressor genes and oncogenes are closely involved in senescence, as their knockdown and ectopic expression confer immortality and senescence induction, respectively. By using high throughput genetic screening to search for genes involved in senescence, several candidate oncogenes and putative tumor suppressor genes have been recently isolated, including subtypes of micro-RNAs. These findings offer new perspectives in the modulation of senescence and open new approaches for cancer therapy.

Figure 1

Primary cells reach replicative senescence after several passages in culture. The passage number where they reach senescence is affected by the tissue conditions, etc. In addition, senescence can be forced to arise upon SIS. A senescence cell can remain arrested for a long period of time. Alternatively, epigenetic changes and/or stochastic mutation/s can lead it to escape from senescence.

Figure 2

Senescence-inducing factors as targets of cancer therapy. Details are described in the text.

Figure 3

Phenotypic aspect of senescence induction from human mammalian epithelial cells (HMEC) immortalized with the TERT telomerase (left panel). HMEC are induced to enter into senescence (right panel). HMEC are fixed and stained with Cell Mask to visualize cell morphology.