As an important component of tumor microenvironment, cancer-associated fibroblasts (CAFs) have lately gained prominence owing to their crucial role in the resistance to therapies. Photodynamic therapy (PDT) stands out as a successful therapeutic strategy to treat cutaneous squamous cell carcinoma. In this study, we demonstrate that the transforming growth factor β1 (TGFβ1) cytokine secreted by CAFs isolated from patients with SCC can drive resistance to PDT in epithelial SCC cells. To this end, CAFs obtained from patients with in situ cSCC were firstly characterized based on the expression levels of paramount markers as well as the levels of TGFβ1 secreted to the extracellular environment. On a step forward, two established human cSCC cell lines (A431 and SCC13) were pre-treated with conditioned medium obtained from the selected CAF cultures. The CAF-derived conditioned medium effectively induced resistance to PDT in A431 cells through a reduction in the cell proliferation rate. This resistance effect was recapitulated by treating with recombinant TGFβ1 and abolished by using the SB525334 TGFβ1 receptor inhibitor, providing robust evidence of the role of TGFβ1 secreted by CAFs in the development of resistance to PDT in this cell line. Conversely, higher levels of recombinant TGFβ1 were needed to reduce cell proliferation in SCC13 cells, and no induction of resistance to PDT was observed in this cell line in response to CAF-derived conditioned medium. Interestingly, we probed that the comparatively higher intrinsic resistance to PDT of SCC13 cells was mediated by the elevated levels of TGFβ1 secreted by this cell line. Our results point at this feature as a promising biomarker to predict both the suitability of PDT and the chances to optimize the treatment by targeting CAF-derived TGFβ1 in the road to a more personalized treatment of particular cSCC tumors.

Exposure to sun and especially to ultraviolet radiation (UVR) exerts well known detrimental effects on skin which are implicated in malignancy. UVR induces production of cyclobutane pyrimidine dimers (CPDs), immediately during exposure and even hours after the exposure, these latter being called dark-CPDs, as consequence of the effects of different reactive species that are formed. Fernblock® (FB), an aqueous extract of Polypodium leucotomos, has proven to have photoprotective and antioxidant effects on skin. The aim of our work was to investigate the potential photoprotective effect of FB against dark-CPD formation. Murine melanocytes (B16-F10) were exposed to UVA radiation and the production of dark-CPDs and different reactive oxygen and nitrogen species (ROS and RNS) was measured. Significant dark-CPD formation could be seen at 3h after UVA irradiation, which was inhibited by the pre-treatment of cells with FB. Formation of nitric oxide, superoxide and peroxynitrite was increased after irradiation, consistent with the increased CPD formation. FB successfully reduced the production of these reactive species. Hence, these results show how dark-CPDs are formed in UVA irradiated melanocytes, and that FB acts as a potential antioxidant and ROS scavenger, preventing the DNA damage induced by sun exposure.

Non-melanoma skin cancer has recently seen an increase in prevalence, and it is estimated that this grow will continue in the coming years. In this sense, the importance of therapy effectiveness has increased, especially photodynamic therapy. Photodynamic therapy has attracted much attention as a minimally invasive, selective and repeatable approach for skin cancer treatment and prevention. Although its high efficiency, this strategy has also faced problems related to tumor resistance, where the tumor microenvironment has gained a well-deserved role in recent years. Tumor microenvironment denotes a wide variety of elements, such as cancer-associated fibroblasts, immune cells, endothelial cells or the extracellular matrix, where their interaction and the secretion of a wide diversity of cytokines. Therefore, the need of designing new strategies targeting elements of the tumor microenvironment to overcome the observed resistance has become evident. To this end, in this review we focus on the role of cancer-associated fibroblasts and tumor-associated macrophages in the resistance to photodynamic therapy. We are also exploring new approaches consisting in the combination of new and old drugs targeting these cells with photodynamic therapy to enhance treatment outcomes of non-melanoma skin cancer.

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Photoaging and carcinogenesis are facilitated by oxidative stress, inflammation, angiogenesis, and extracellular matrix (ECM) remodeling. Oxidative effects include DNA damage, membrane oxidation, lipid peroxidation, and alterations in the expression of p53 and antioxidant enzymes. The inflammatory and angiogenesis mediators include interleukin-1, tumor necrosis factor-α, interleukin-8, transforming growth factor-β, and vascular endothelial growth factor. ECM remodeling includes alterations in the expression and organization of collagen, elastin, matrix metalloproteinases, and elastase. 1α, 25-dihydroxy-vitamin D3 has antioxidant, anti-inflammatory, and ECM regulatory properties, and can counteract the processes that facilitate photoaging and carcinogenesis. This review provides an overview of the beneficial effects of vitamin D supplementation at a molecular level, followed by a brief discussion regarding its use as a supplement.

Oxidative stress is a harmful effect induced on the skin by polycyclic aromatic hydrocarbons (PAH), including benzo[a]pyrene (BaP) air pollutants. This effect is amplified by the additive damaging effect of the sun, especially through the UVA light component. Besides being one of the main compounds that make up air pollution, BaP can also be found in tar, tobacco smoke, and various foods. In addition to its direct carcinogenic potential, BaP can act as a photosensitizer absorbing sunlight in the UVA range and thus generating ROS and 8-hydroxy-2′-deoxyguanosine (8-OHdG). Fernblock® (FB) is an aqueous extract from the leaves of Polypodium leucotomos that has been proven to exert photoprotective and antioxidant effects on skin cells. In this study, we evaluate the potential of FB to prevent the damage induced by a combination of BaP and UVA light on human keratinocyte and mouse melanocyte cell lines (HaCaT and B16-F10, respectively). In particular, we have analyzed the capacity of FB to counteract the alterations caused on cellular morphology, viability, oxidative stress and melanogenic signaling pathway activation. Our data indicate that FB prevented cell damage and reduced oxidative stress and melanogenic signaling pathway activation caused by a combination of BaP and UVA light irradiation. Altogether, our findings support the fact that FB is able to prevent skin damage caused by the exposure to a combination of UVA and the air pollutant BaP.

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