Cancer and aging: a model for the cancer promoting effects of the aging stroma

The incidence of cancer rises exponentially with age in humans and many other mammalian species. Malignant tumors are caused by an accumulation of oncogenic mutations. In addition, malignant tumorigenesis requires a permissive tissue environment in which mutant cells can survive, proliferate, and express their neoplastic phenotype. We propose that the age-related increase in cancer 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 the epithelial cells of renewable tissues. An important element of epithelial tissues is the stroma, the sub-epithelial layer composed of extracellular matrix and several cell types. The stroma is maintained, remodeled and repaired by resident fibroblasts, supports and instructs the epithelium, and is essential for epithelial function. One change that occurs in tissues during aging is the accumulation of epithelial cells and fibroblasts that have undergone cellular senescence. Cellular senescence irreversibly arrests proliferation in response to damage or stimuli that put cells at risk for neoplastic transformation. Senescent cells secrete factors that can disrupt tissue architecture and/or stimulate nearby cells to proliferate. We therefore speculate that their presence may create a pro-oncogenic tissue environment that synergizes with oncogenic mutations to drive the rise in cancer incidence with age. Recent evidence lends support to this idea, and suggests that senescent stromal fibroblasts may be particularly adept at creating a tissue environment that can promote the development of age-related epithelial cancers.