Figure. The two anticancer mechanisms of cellular senescence/crisis. (Right) If an oncogenic mutation triggers senescence, a potential cancer is prevented. (Left) If senescence becomes impossible because of inactivated checkpoints, telomere-based crisis and cell death may ensue. If telomerase or alternative lengthening of telomeres (ALT) becomes activated before or during crisis, an immortal clone arises that has already acquired malignant properties or is on its way to full malignancy.

Senescence was originally described as a terminal nondividing state of normal human cells reached after many cell divisions in culture. The cause was shown to be shortening of telomeres, leading to telomere dysfunction and cell cycle arrest. Subsequently, a more rapid, nontelomere-dependent form of senescence, often termed stress-induced premature senescence, was described. Most importantly, it occurs in response to activated oncogene products. Oncogene-induced senescence has been shown to play a role in tumor suppression in vivo; it does not seem to involve changes in telomeres. A second phenomenon that plays a role in tumor suppression, which does involve progressive telomere shortening, is crisis, the state that cells reach when cell cycle checkpoints are impaired and cells can no longer respond to telomere shortening oroncogene activation by entering senescence. These two processes, oncogene-induced senescence and telomere-based crisis, exert powerful anticancer effects.

Research on Senescence and Cancer is a joint program of the Barshop Institute and the Cancer Therapy and Research Center at UTHSCSA. Within CTRC, interested faculty have formed a working group on Senescence and Cancer (within the Cancer Development and Progression Program, Aging and Cancer Theme). Any faculty interested in participating in this Working Group are invited to contact Dr. Peter Hornsby. Dr. Hornsby's research concerns the influence of senescence on cancer in a xenograft model in profoundly immunodeficient RAG2^-/-/γc^-/- mice. In a collaboration with Dr. Rong Li, his lab is studying factors secreted by senescent cells that alter the properties of cancer cells. It is increasingly recognized that stromal cells, particularly adipose stromal cells, are major determinants of cancer behavior in vivo. Dr. Hornsby is also studying the role of senescence in the extraordinary cancer resistance of the naked mole-rat, one of the model organisms under intensive study at the Barshop Institute. Dr. Zhi-min Yuan's lab has a very active program of study of the influence of senescence on the growth of breast cancer cells. His lab employs a novel 3-dimensional culture model in which breast cancer cells and their normal counterparts develop as true tissue structures under controlled conditions in the lab.