The dark side of daylight: photoaging and the tumor microenvironment in melanoma progression

Abstract

Continued thinning of the atmospheric ozone, which protects the earth from damaging ultraviolet radiation (UVR), will result in elevated levels of UVR reaching the earth's surface, leading to a drastic increase in the incidence of skin cancer. In addition to promoting carcinogenesis in skin cells, UVR is a potent extrinsic driver of age-related changes in the skin known as "photoaging." We are in the preliminary stages of understanding of the role of intrinsic aging in melanoma, and the tumor-permissive effects of photoaging on the skin microenvironment remain largely unexplored. In this Review, we provide an overview of the impact of UVR on the skin microenvironment, addressing changes that converge or diverge with those observed in intrinsic aging. Intrinsic and extrinsic aging promote phenotypic changes to skin cell populations that alter fundamental processes such as melanogenesis, extracellular matrix deposition, inflammation, and immune response. Given the relevance of these processes in cancer, we discuss how photoaging might render the skin microenvironment permissive to melanoma progression.

Figure 1. Similar and diverging features of the hallmarks of aging and cancer.

There are many features of the hallmarks of aging, as described in ref. and ref. , that can lead to changes in the microenvironment that are permissive of tumor growth. Persistent alterations to intercellular communication and deregulated nutrient signaling that arise with aging can promote proliferative signaling and evasion of growth suppression, both of which are hallmarks of cancer as described in ref. . Additional features equivalent between these two processes include genomic instability, deregulated cell energy processes, and chronic inflammation. However, unlike cancer, the aging cell population is also characterized by mechanisms that shorten cellular lifespan, such as stem cell exhaustion, cellular senescence, and telomere attrition. In contrast, cancer cells acquire the ability to constitutively activate prosurvival pathways that resist cell death and allow the transformed cells to avoid immune destruction and to enable replicative immunity. The hallmarks listed in the shaded areas were previously described as unique to aging or cancer.

Figure 2. Immunosuppression associated with UV-mediated photoaging.

As a direct result of UVR, several immunosuppressive factors are produced. These include cis-UCA; vitamin D; platelet-activating factor receptor (PAF-R) agonists and platelet-like ligands; and AhR ligands such as FICZ. These factors cause the release of cytokines such as histamine, prostaglandin E₂ (PGE₂), TNF, and IL-10 (198) and IL-33 (199) from mast cells and keratinocytes and influence the differentiation of CD4⁺ T cells to an immunosuppressive phenotype. Vitamin D influences the differentiation of monocytes to macrophages and DCs by downregulating the vitamin D receptor, resulting in decreased DC maturation; and by downregulating costimulatory molecules, thus reducing antigen-presenting ability. Vitamin D is also reported to influence immunosuppression via keratinocytes, Tregs, and mast cells. Cis-UCA has potent immunosuppressive effects mediated through numerous dermal cells via the serotonin receptor on, but not limited to, mast cells and keratinocytes. Cis-UCA interacts with dermal mast cells to frequently induce degranulation of both histamine and PGE₂. Cis-UCA is able to stimulate the release of TNF-α from keratinocytes, preventing Langerhans cells from migrating to lymph nodes and presenting antigen to T cells; as well as to stimulate production of PGE₂. UV-mediated damage to keratinocytes produces PAFs to also release PGE₂, as well as IL-10 and TNF. Absorption of UVB by tryptophan produces AhR ligands, including FICZ and TCDD, that signal through keratinocytes and T cells. AhR ligands upregulate COX-2 in keratinocytes, resulting in increased production of PGE₂, which influences the recruitment of Tregs. AhR ligands also influence T cells via adaptive and regulatory-like T cells (induced Tregs and Tr1 cells). AhR ligands enhance the production of IL-10 from naive CD4⁺ T cells. AhR ligands along with TGF-β are also able to induce suppressive T cell phenotypes via the upregulation of FOXP3 either via Smad1 or potentially via direct binding of AhR to the FOXP3 promoter.

Figure 3. Differences between the chronologically aged and photoaged skin microenvironments.

A summary of key differences between chronologically aged (A) and photoaged (B) skin as described in “The photoaged microenvironment and melanoma progression.” Intrinsic aging is associated with decreases in melanocyte proliferation and melanogenesis, resulting in hypopigmentation of the epidermis. In contrast, UVR-exposed keratinocytes induce melanogenesis, thereby causing regions of hyperpigmentation clinically recognized as “sun spots.” Both the intrinsically aged and the photoaged fibroblasts of the dermal skin layer express SASP and increased production of MMPs, which leads to collagen breakdown and ECM remodeling. The mechanisms driving spontaneous collagen fragmentation in intrinsically aged skin remain largely unknown. However, in photoaged fibroblasts, this process is thought to be mediated by an increased hyaluronic acid depolymerization by HYBID and downregulation of collagen production by altered miRNAs and circRNAs.