Unraveling the interplay between senescent dermal fibroblasts and cutaneous squamous cell carcinoma cell lines at different stages of tumorigenesis

Abstract

Cutaneous Squamous Cell Carcinoma (cSCC) is the second most common type of non-melanoma skin cancer in white-skinned populations. cSCC is associated with sun exposure and aging, which is concomitant with an accumulation of senescent cells in the skin. The involvement of senescent cells in carcinogenesis has been highlighted in several cancer types and an interaction between cSCC cells and senescent cells is proposed, but still little explored. Tumor-associated effects are mostly attributed to the senescence-associated secretory phenotype (SASP). Here, we compared two in vitro models of senescence, namely replicative senescence and UVB-stress induced premature senescence (UVB-SIPS), in human dermal fibroblasts and screened for expression of SASP-related genes in our models. Next, the impact of senescent fibroblasts on three cSCC isogenic cell lines, representing different stages of keratinocyte malignant transformation, was studied. Only a limited impact on cSCC cell lines' growth and migration has been detected with conditioned media collected from senescent fibroblasts and indirect co-cultures. We then investigated the opposite interaction and found that cSCC cell lines maintained in indirect co-cultures with fibroblasts induced and reinforced their senescence state as shown by an increased proportion of cells positive for the senescence-associated β-galactosidase activity and an increased expression of several SASP-related genes. Moreover, these effects were modulated according to the stage of tumorigenesis of the different cSCC cell lines used. Finally, cSCC cell lines-co-cultures are associated with NF-κB activation in HDFs. Understanding the interplay between tumor cells and their microenvironment may have important influences in cancer research and therapeutic strategies.

Modeling transcriptomic age using knowledge-primed artificial neural networks

“…Irrespective of this, the data shows that the clock not only accurately captures aging in vivo but also models processes that define aging in vitro, adding to its utility. The sensitivity of the model towards senescence also delivers one potential mechanism explaining the pronounced age acceleration predicted by the model for the AK and SCC signatures, as an accumulation of senescent cells is not only a feature of aging tissues but also frequently observed in precancerous and cancerous lesions, including AKs and SCCs 47 , 48 .…”

Growth factors‐based platelet lysate rejuvenates skin against ageing through NF‐κB signalling pathway: In vitro and in vivo mechanistic and clinical studies

“… 70 The NF‐κB‐activated SASP factors, such as IL‐6, IL‐8 and MMPs, induce paracrine DNA damage, chronic inflammation and senescence of healthy neighbouring cells, resulting in acceleration of ageing. 71 , 72 , 73 Therapeutic inhibition of overexpressed SASP factors (IL‐6, IL‐8, MMP‐1 and MMP‐9) of senescent HDFs could reverse inflammatory response and promote skin rejuvenation. 74 , 75 , 76 By using P65 blocker (P65 siRNA) and P65 agonist (prostratin), this study confirmed the NF‐κB pathway‐dependent anti‐ageing mechanism of hPL.…”

“…SASP is the main characteristics of cellular senescence, containing specific pro‐inflammatory and senescence messaging secretome 70 . The NF‐κB‐activated SASP factors, such as IL‐6, IL‐8 and MMPs, induce paracrine DNA damage, chronic inflammation and senescence of healthy neighbouring cells, resulting in acceleration of ageing 71–73 . Therapeutic inhibition of overexpressed SASP factors (IL‐6, IL‐8, MMP‐1 and MMP‐9) of senescent HDFs could reverse inflammatory response and promote skin rejuvenation 74–76 .…”

Alpha-Tocopherol Protects Human Dermal Fibroblasts by Modulating Nitric Oxide Release, Mitochondrial Function, Redox Status, and Inflammation

“…While in physiologic conditions, they are almost resting, in the presence of any skin injury, they show abnormalities in the metabolism and proliferation, which can be at the basis of aging skin structure changes [30,31]. Even more relevant is the involvement of the senescent fibroblasts not only in the early stages of skin carcinogenesis [32] but also in cancer cell migration and metastasis, both in melanoma [33] and in NMSC [34]. Therefore, the preservation of their functionality can be a strategy in the prevention of intrinsic and extrinsic skin aging and even cutaneous carcinogenesis [35,36].…”