title: 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.
authors.affiliation: Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: L
authors.initials: L
authors.lastname: Golomb
authors.affiliation: Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: A
authors.initials: A
authors.lastname: Sagiv
authors.affiliation: Molecular Carcinogenesis Group, Department of Histology-Embryology, School of Medicine, University of Athens, Athens, Greece.
authors.forename: I S
authors.initials: IS
authors.lastname: Pateras
authors.affiliation: Hadassah Medical School, The Hebrew University, Jerusalem, Israel.
authors.forename: A
authors.initials: A
authors.lastname: Maly
authors.affiliation: Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: V
authors.identifier: http://orcid.org/0000-0002-3977-5482
authors.initials: V
authors.lastname: Krizhanovsky
authors.affiliation: Department of Histology-Embryology, Medical School, National Kapodistrian University of Athens, 75 Mikras Asias Str., Goudi, 11527 Athens, Greece.|Biomedical Research Foundation, Academy of Athens, 4 Soranou Efessiou, 11527 Athens, Greece.|Faculty Institute for Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, Manchester M13 9WL, UK.|Manchester Centre for Cellular Metabolism, University of Manchester, Manchester Academic Health Science Centre, Manchester M13 9WL, UK.
authors.forename: V G
authors.initials: VG
authors.lastname: Gorgoulis
authors.affiliation: Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: M
authors.initials: M
authors.lastname: Oren
authors.affiliation: Hadassah Medical School, The Hebrew University, Jerusalem, Israel.
authors.forename: A
authors.initials: A
authors.lastname: Ben-Yehuda
mesh_terms: D000375:Aging / Q000502:physiology*; D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology; D016922:Cellular Senescence / Q000235:genetics / Q000502:physiology; D011905:Genes, ras / Q000235:genetics / Q000502:physiology*; D007249:Inflammation / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012878:Skin Neoplasms / Q000378:metabolism / Q000473:pathology*