Integrating epithelial cancer, aging stroma and cellular senescence

Cancer incidence rises exponentially with age in humans and many other mammalian species. At least two critical changes are essential in order for cancer to develop: an accumulation of oncogenic mutations and a permissive tissue environment in which mutant cells can survive, proliferate, and express their neoplastic phenotype. Increasing evidence suggests that the rise in cancer with age results from a synergy between the accumulation of mutations and age-related, pro-oncogenic changes in the tissue milieu. Most age-related cancers derive from epithelial cells. Epithelial tissues are supported by a stroma, which is composed of extracellular matrix and several cell types. The stroma is essential for the function of the epithelium, and is maintained, remodeled and repaired by fibroblasts. One age-related change that occurs in epithelial tissues is the accumulation of senescent cells. Cellular senescence is a potent tumor suppressive mechanism that irreversibly arrests proliferation in response to damage or stimuli that put cells at risk for neoplastic transformation. Senescent cells, particularly senescent stromal fibroblasts, secrete factors that can disrupt tissue architecture and/or stimulate neighboring cells to proliferate. We suggest that senescent cells can create a tissue environment that synergizes with oncogenic mutations to promote the progression of age-related cancers. Recent evidence lends support to this idea, and suggests that cellular senescence may be an example of evolutionary antagonistic pleiotropy.