Contact Inhibition, Cancer, and Cellular Senescence
The phenomenon of contact inhibition is of importance in resisting cancer, and also appears to influence cellular senescence. Both of these topics are of considerable interest to researchers working on in aging and longevity, and the more so since it seems that naked mole rat cancer immunity appears to be based on more effective contact inhibition. One has to wonder whether this also contributes to their considerable longevity as well, perhaps via suppression of cellular senescence.
During cell cycle arrest caused by contact inhibition (CI), cells do not undergo senescence, thus resuming proliferation after replating. The mechanism of senescence avoidance during CI is unknown. Recently, it was demonstrated that the senescence program, namely conversion from cell cycle arrest to senescence (i.e., geroconversion), requires mammalian target of rapamycin (mTOR). Geroconversion can be suppressed by serum starvation, rapamycin, and hypoxia, which all inhibit mTOR.Here we demonstrate that CI, as evidenced by p27 induction in normal cells, was associated with inhibition of the mTOR pathway. Furthermore, CI antagonized senescence caused by CDK inhibitors. Stimulation of mTOR in contact-inhibited cells favored senescence. In cancer cells lacking p27 induction and CI, mTOR was still inhibited in confluent culture as a result of conditioning of the medium. This inhibition of mTOR suppressed p21-induced senescence. Also, trapping of malignant cells among contact-inhibited normal cells antagonized p21-induced senescence.
Thus, we identified two nonmutually exclusive mechanisms of mTOR inhibition in high cell density: (i) CI associated with p27 induction in normal cells and (ii) conditioning of the medium, especially in cancer cells. Both mechanisms can coincide in various proportions in various cells. Our work explains why CI is reversible and, most importantly, why cells avoid senescence in vivo, given that cells are contact-inhibited in the organism.