Age-associated inflammation connects RAS-induced senescence to stem cell dysfunction and epidermal malignancy

Abstract

Aging is the single biggest risk factor for malignant transformation. Among the most common age-associated malignancies are non-melanoma skin cancers, comprising the most common types of human cancer. Here we show that mutant H-Ras activation in mouse epidermis, a frequent event in cutaneous squamous cell carcinoma (SCC), elicits a differential outcome in aged versus young mice. Whereas H-Ras activation in the young skin results in hyperplasia that is mainly accompanied by rapid hair growth, H-Ras activation in the aged skin results in more dysplasia and gradual progression to in situ SCC. Progression is associated with increased inflammation, pronounced accumulation of immune cells including T cells, macrophages and mast cells as well as excessive cell senescence. We found not only an age-dependent increase in expression of several pro-inflammatory mediators, but also activation of a strong anti-inflammatory response involving enhanced IL4/IL10 expression and immune skewing toward a Th2 response. In addition, we observed an age-dependent increase in the expression of Pdl1, encoding an immune suppressive ligand that promotes cancer immune evasion. Moreover, upon switching off oncogenic H-Ras activity, young but not aged skin regenerates successfully, suggesting a failure of the aged epidermal stem cells to repair damaged tissue. Our findings support an age-dependent link between accumulation of senescent cells, immune infiltration and cancer progression, which may contribute to the increased cancer risk associated with old age.

Type XVII collagen coordinates proliferation in the interfollicular epidermis

“…The accumulation of Ki-67-positive cells and prolonged hyperplasia in the aged epidermis during recovery from carcinogenic treatments has been reported (Golomb et al, 2015). It would be intriguing to observe skin carcinogenesis upon COL17 deficiency, as its relevance in colon and lung cancers has been described (Liu et al, 2016a, 2016b; Moilanen et al, 2015).…”

Arterial ageing: from endothelial dysfunction to vascular calcification

“…One of the results of such dysregulation is that the plasma concentrations of inflammatory proteins can increase with age in healthy individuals , including proinflammatory cytokines such as interleukin (IL)‐6, tumour necrosis factor alpha (TNF‐α) and monocyte chemoattractant protein‐1 (MCP‐1) . Therefore, their upregulation in advanced ageing underlies a low‐grade, chronic, systemic proinflammatory state correlated with age‐associated diseases such as diabetes and obesity .…”

The Senescence-Associated Secretory Phenotype: Critical Effector in Skin Cancer and Aging

“…Further, a recent study demonstrated that activation of oncogenic Hras in the mouse epidermis has differential effects in young and old skin. Although young mice develop epidermal hyperplasia, old mice develop tumors consistent with SCC along with increased numbers of proinflammatory cytokines (Golomb et al, 2015). In a mouse model of cutaneous SCC, cancer-associated fibroblasts induce SASP-like inflammation, angiogenesis, and tumor growth through an NF-κB-mediated mechanism, reinforcing the links between the SASP and tumorigenesis in the skin (Erez et al, 2010).…”