Abstract
Aging is associated with a rising incidence of cutaneous squamous cell carcinoma (cSCC), an aggressive skin cancer with the potential for local invasion and metastasis. Acquisition of a senescence-associated secretory phenotype (SASP) in dermal fibroblasts has been postulated to promote skin cancer progression in elderly individuals. The underlying molecular mechanisms are largely unexplored. We show that Chemerin, a previously unreported SASP factor released from senescent human dermal fibroblasts, promotes cSCC cell migration, a key feature driving tumor progression. Whereas the Chemerin abundance is downregulated in malignant cSCC cells, increased Chemerin transcripts and protein concentrations are detected in replicative senescent fibroblasts in vitro and in the fibroblast of skin sections from old donors, indicating that a Chemerin gradient is built up in the dermis of elderly. Using Transwell® migration assays, we show that Chemerin enhances the chemotaxis of different cSCC cell lines. Notably, the Chemerin receptor CCRL2 is remarkably upregulated in cSCC cell lines and human patient biopsies. Silencing Chemerin in senescent fibroblasts or the CCRL2 and GPR1 receptors in the SCL-1 cSCC cell line abrogates the Chemerin-mediated chemotaxis. Chemerin triggers the MAPK cascade via JNK and ERK1 activation, whereby the inhibition impairs the SASP- or Chemerin-mediated cSCC cell migration.Taken together, we uncover a key role for Chemerin, as a major factor in the secretome of senescent fibroblasts, promoting cSCC cell migration and possibly progression, relaying its signals through CCRL2 and GPR1 receptors with subsequent MAPK activation. These findings might have implications for targeted therapeutic interventions in elderly patients.
Highlights
Cutaneous squamous cell carcinoma represents the second most common type of skin cancer worldwide with increasing incidence in elderly individuals [1]. cutaneous squamous cell carcinoma (cSCC) develops through a multistep process, in which the accumulation of mutations and genetic alterations mainly drive the initiation step [2], while the cellular and molecular alterations of the surrounding microenvironment support the promotion and progression steps [3]
As the incidence of cSCCs increases with age and senescent fibroblasts have been suggested to play a causal role in cSCC progression, we investigated the paracrine effects of senescent human dermal fibroblasts (HDFs) on cSCC cell migration and invasion
To a different extent, a robust migratory response of different cSCC cell lines was induced by conditioned medium (CM) of senescent fibroblasts of different strains (Figure 1C), these data indicate that the observed enhanced migratory response is similar for all tested cSCC cell lines and senescent fibroblast strains and most likely constitutes a general mechanism of senescence-associated secretory phenotype (SASP)-induced migration
Summary
Cutaneous squamous cell carcinoma (cSCC) represents the second most common type of skin cancer worldwide with increasing incidence in elderly individuals [1]. cSCC develops through a multistep process, in which the accumulation of mutations and genetic alterations mainly drive the initiation step [2], while the cellular and molecular alterations of the surrounding microenvironment support the promotion and progression steps [3]. Exposure to ultraviolet (UV) radiation is the main cause for DNA damage and mutations in epidermal keratinocytes as well as in dermal fibroblasts underneath the epidermis [4, 5]. Mutations in the epidermal stem/progenitor cells affecting oncogenes like Ras or tumor suppressor genes such as p53 are www.impactjournals.com/oncotarget frequently causal for cSCC initiation [2]. The DNA damage response pathways in dermal fibroblasts lead to the activation of p53 and p16INK4a and induction of cellular senescence. It has been proposed that the activation of oncogenic Ras in aged murine skin causes excessive cellular senescence, epidermal stem cell dysfunction, enhanced inflammation, and immune cell skewing towards a T helper cell type 2, eventually resulting in epidermal dysplasia and cSCC progression [11]
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