TGFβ Signaling in Photoaging and UV-Induced Skin Cancer

Abstract

UVR is a major etiology for premature skin aging that leads to photoaging and UV-induced skin cancers. In the skin, TGFβ signaling is a growth inhibitor for keratinocytes and a profibrotic factor in the dermis. It exerts context-dependent effects on tumor progression. Chronic UV exposure likely causes TGFβ1/SMAD3 signaling activation and contributes to metalloproteinase-induced collagen degradation and photoinflammation in photoaging. UV irradiation also causes gene mutations in key elements of the TGFβ pathway, including TGFβRI, TGFβRII, SMAD2, and SMAD4. These mutations enable tumor cells to escape from TGFβ-induced growth inhibition and induce genomic instability and cancer stem cells, leading to the initiation, progression, invasion, and metastasis of cutaneous squamous cell carcinoma (cSCC). Furthermore, UV-induced mutations cause TGFβ overexpression in the tumor microenvironment (TME) of cSCC, basal cell carcinoma (BCC), and cutaneous melanoma, resulting in inflammation, angiogenesis, cancer-associated fibroblasts, and immune inhibition, supporting cancer survival, immune evasion, and metastasis. The pleiotropic effects of TGFβ provide possible treatment options for photoaging and skin cancer. Given the high UV-induced mutational burden and immune-repressive TME seen in cSCC, BCC, and cutaneous melanoma, treatment with the combination of a TGFβ signaling inhibitor and immune checkpoint blockade could reverse immune evasion to reduce tumor growth.

Figure 1.. Skin morphology changes in UV-induced premature aging and UV-induced skin cancer.

Chronic UV exposure induces DNA damage and ROS accumulation in the skin. These detrimental factors cause decreased and fragmented collagen and elastic fibers in the dermis that lead to photoaging. Meanwhile, UV radiation generates photoproduct CPDs that cause UV-signature DNA mutations in keratinocytes and epidermal stem cells. These mutations result in cancer initiation and contribute to an inflammatory, angiogenic, and immune inhibitive tumor microenvironment (TME) that supports the progression, invasion, and metastasis of cSCC, BCC, and cutaneous melanoma. ROS, reactive oxygen species; CPDs, cyclobutane pyrimidine dimers; cSCC, cutaneous squamous cell carcinoma; BCC, basal cell carcinoma.

Figure 2.. The role of TGFβ signaling in the pathogenesis of photoaging and UV-induced skin cancer.

During photoaging, keratinocyte-derived TGFβ production induces photo-inflammation by MMP2, MMP9, and the recruitment of neutrophils, Meanwhile, fibroblasts in the dermis activate TGFβ/Smad3 signaling to induce a fibrotic response. These effects cause damage to collagen fibrils and formation of solar elastosis. In UV-induced skin cancer, TGFβ in the TME activates keratinocytes and endothelial cells, and promotes the generation of CAFs and represses immune cell functions, leading to a TME that favors tumor growth, invasion, and metastasis.