The evolution of multi-cellular life is in essence the story of a tooth and nail struggle with cancer, one that continues even now. Complex structure, regeneration, and growth are all required in higher forms of life, but that combination means that any sort of sustained breakdown in control over cell proliferation tends to be fatal because it disrupts necessary structures. Multiple layered systems, within cells and outside them, have evolved to try to block damaged cells from uncontrolled proliferation, ranging from tumor suppressor genes to the surveillance of the immune system and its destruction of potentially cancerous cells. Cellular senescence is one of these strategies, and like all of them, it is only somewhat successful. With only a few rare exceptions, evolution has curbed cancer risk to the minimum degree needed for a species to survive, no more than that.
Cellular senescence is, of course, one of the causes of aging. Cells become senescence in response to damage, a toxic environment, or at the end of their replicative life span, and near all destroy themselves or are destroyed by the immune system. Enough linger to cause problems, however, producing the senescence-associated secretory phenotype (SASP) that disrupts tissue structure and function. Cellular senescence is an anti-cancer strategy because senescence locks down a cell to prevent replication - so it should function to remove the most at-risk cells before they can run off the rails. Indeed, this works in the early stages of life. But with enough senescent cells lurking in a tissue, the SASP changes the environment to make it much more amenable to cancer: inflammatory, pro-growth, with increased levels of cell damage. Ultimately, cellular senescence becomes an enabler of cancer.
Cellular senescence describes an irreversible growth arrest characterized by distinct morphology, gene expression pattern, and secretory phenotype. The final or intermediate stages of senescence can be reached by different genetic mechanisms and in answer to different external and internal stresses. It has been maintained in the literature but never proven by clearcut experiments that the induction of senescence serves the evolutionary purpose of protecting the individual from development and growth of cancers. This hypothesis was recently scrutinized by new experiments and found to be partly true, but part of the gene activities now known to happen in senescence are also needed for cancer growth, leading to the view that senescence is a double-edged sword in cancer development.
In current cancer therapy, cellular senescence is, on the one hand, induced deliberately in tumor cells, as thereby the therapeutic outcome is improved, but might, on the other hand, also be induced unintentionally in non-tumor cells, causing inflammation, secondary tumors, and cancer relapse. Importantly, aging leads to accumulation of senescent cells in tissues and organs of aged individuals. Senescent cells can occur transiently, e.g., during embryogenesis or during wound healing, with beneficial effects on tissue homeostasis and regeneration or accumulate chronically in tissues, which detrimentally affects the microenvironment by dedifferentiation or transdifferentiation of senescent cells and their neighboring stromal cells, loss of tissue specific functionality, and induction of the senescence-associated secretory phenotype, an increased secretory profile consisting of pro-inflammatory and tissue remodeling factors.
These factors shape their surroundings toward a pro-carcinogenic microenvironment, which fuels the development of aging-associated cancers together with the accumulation of mutations over time. Among well-documented stress situations and signals which induce senescence, oncogene-induced senescence and stress-induced premature senescence are prominent. New findings about the role of senescence in tumor biology suggest that cancer therapy should leverage genetic and pharmacological methods to prevent senescence or to selectively kill senescent cells in tumors.