Cells that have divided too many times or are damaged become senescent, removing themselves from the cell cycle as a protective measure that reduces the risk of cancer by preventing damaged cells from being active. Senescent cells should be destroyed, either by the immune system or by the mechanisms of programmed cell death, but some evade this fate and their numbers grow with age. These cells exhibit a range of damaging behaviors: promoting senescence in surrounding cells, releasing compounds that harm nearby tissue structure, and so forth. Sadly, and despite their role in cancer suppression, they also serve to increase the risk of cancer:
Senescence is assumed to be a cell-autonomous tumor-suppressor mechanism, because it is accompanied by irreversible cell-cycle arrest occurring mainly in response to irreparable telomeric and non-telomeric DNA damage. This has been especially well demonstrated for fibroblasts, the major cell component of the stroma. Yet fibroblast senescence may contribute to promoting cancer development and evolution, in a non-cell-autonomous, paracrine way, as suggested by the observation that senescent fibroblasts can stimulate growth, the epithelial-mesenchymal transition (EMT), and invasiveness of premalignant and malignant cells. This results from the fact that senescing fibroblasts develop a senescence-associated secretory phenotype (SASP) similar to that of carcinoma-associated fibroblasts, characterized by increased expression and secretion of growth factors, inflammatory cytokines, and matrix metalloproteinases.
We investigated here whether the senescent fibroblast secretome might have an impact on the very first stages of carcinogenesis. We chose the cultured normal primary human epidermal keratinocyte model, because after these cells reach the senescence plateau, cells with transformed and tumorigenic properties systematically and spontaneously emerge from the plateau. In the presence of medium conditioned by autologous senescent dermal fibroblasts, a higher frequency of post-senescence emergence was observed and the post-senescence emergent cells showed enhanced migratory properties and a more marked epithelial-mesenchymal transition. Using pharmacological inhibitors, siRNAs, and blocking antibodies, we demonstrated that the MMP-1 and MMP-2 matrix metalloproteinases, known to participate in late stages of cancer invasion and metastasis, are responsible for this enhancement of early migratory capacity. We present evidence that MMPs act by activating the protease-activated receptor 1 (PAR-1), whose expression is specifically increased in post-senescence emergent keratinocytes.
Developing the means to periodically clear out and destroy senescent cells is a necessary part of any future package of rejuvenation therapies, such as those of the SENS research program. Good progress is being made in targeted cell killing technologies by the cancer research community, and there are a number of possible mechanisms that might be used to distinguish senescent cells from healthy cells, so this type of therapy looks very feasible from a technical perspective.