Figure 1. Determining the role of stromal cell senescence and inflammation in initiation of epithelial carcinogenesis.

(A) Surface epithelial tissues like those of the bronchial tree, bladder or skin are exposed to and protected from environmental stressors and carcinogens like smoke, kidney-secreted toxic chemicals, γ-irradiation and UV light. Pro-oncogenic gene mutations induced by these agents are however not sufficient to elicit the carcinogenic process with senescence of oncogene-bearing epithelial cells as a counteracting induced mechanism. The impact of environmental stressors extends however to the underlying stroma, with induction of stromal cell senescence and recruitment of a chronic inflammatory infiltrate as consequences that reinforce each other. (B) Fibroblast senescence produces large amounts of diffusible growth factors, cytokines, and matrix remodeling enzymes (SASP). In addition, chronic inflammation (with prevalent M2 macrophages and Th1 T cells) generates highly reactive small molecular weight molecules (ROS, RNS). Collectively, these factors impinge on the overlying epithelium, with mitogenic and chromosome-destabilizing effects, thus promoting tumorigenic outgrowth. As discussed in this review, an emerging concept is that approaches aimed at suppressing stromal cell senescence and chronic inflammation could be of substantial value for preventing or reversing early stages of epithelial cancer.