Senescent Fibroblasts Enhance Early Skin Carcinogenic Events via a Paracrine MMP-PAR-1 Axis

Abstract

The incidence of carcinoma increases greatly with aging, but the cellular and molecular mechanisms underlying this correlation are only partly known. It is established that senescent fibroblasts promote the malignant progression of already-transformed cells through secretion of inflammatory mediators. 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. The physiopathological relevance of these results was tested by analyzing MMP activity and PAR-1 expression in skin sections. Both were higher in skin sections from aged subjects than in ones from young subjects. Altogether, our results suggest that during aging, the dermal and epidermal skin compartments might be activated coordinately for initiation of skin carcinoma, via a paracrine axis in which MMPs secreted by senescent fibroblasts promote very early epithelial-mesenchymal transition of keratinocytes undergoing transformation and oversynthesizing the MMP-activatable receptor PAR-1.

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

“…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). Consistent with these findings and a role for the SASP in skin carcinogenesis, inhibition of MMPs can prevent skin cancer invasion (Malaquin et al, 2013; Woenne et al, 2010). And finally, very recent work by Kaur et al (2016) found that aged fibroblasts in the melanoma tumor microenvironment can secrete a Wnt antagonist, sFRP2, that can drive angiogenesis, metastasis, and resistance to targeted therapies such as vemurafenib.…”

Gingival crevicular fluid levels of protease‐activated receptors type 1 and type 2 in diabetic patients with periodontitis

“…PAR 1 upregulation may be explained by the higher mean age of the diabetic patients compared to the systemically healthy patients, as there is a growing body of evidence indicating that changes in the transcriptional and post‐transcriptional regulation are associated with aging. In fact, a recent study by Malaquin et al ., have shown that aging is associated with an increased expression of PAR 1 in the skin . This result may also be explained by the fact that AGEs in diabetics increase the production of thrombin , which may trigger the thrombin–PAR 1 axis with an ultimate enhancement of PAR 1 expression .…”

DNA Damage: From Chronic Inflammation to Age-Related Deterioration

“…Persistent DNA damage and DDR signaling triggers senescent cells to secrete immunomodulatory proteins, a phenomenon known as the senescence-associated secretory phenotype (SASP) (Campisi and d'Adda di Fagagna, 2007; Fumagalli and d'Adda di Fagagna, 2009). SASP factors range from inflammatory and immune-modulatory cytokines to chemokines as well as growth factors, shed cell surface molecules, survival factors and extracellular matrix remodeling enzymes (Coppé et al, 2008; Ohanna et al, 2011; Acosta et al, 2013; Malaquin et al, 2013). Together, they impinge on cell-fate decisions in neighboring cells or the tissue microenvironment.…”