TGFβ Signaling in Photoaging and UV-Induced Skin Cancer

UVR is a major etiology for premature skin aging that leads to photoaging and UV-induced skin cancers. In the skin, TGF beta 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 TGF beta 1/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 TGF beta pathway, including TGF beta RI, TGF beta RII, SMAD2, and SMAD4. These mutations enable tumor cells to escape from TGF beta-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 TGF beta 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 TGF beta 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 TGF beta signaling inhibitor and immune checkpoint blockade could reverse immune evasion to reduce tumor growth.

Automated summary

UVR-induced TGF-beta signaling activation and gene mutations play significant roles in photoaging and the development of skin cancer.