TGFβ Signaling in Photoaging and UV-Induced Skin Cancer

• Published in: Journal of investigative dermatology Vol. 141; no. 4; pp. 1104 - 1110
• Main Authors: Ke, Yao, Wang, Xiao-Jing
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.04.2021
• Subjects: Animals; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Genomic Instability - radiation effects; Humans; Immune Checkpoint Inhibitors; Keratinocytes - drug effects; Keratinocytes - pathology; Keratinocytes - radiation effects; Mice; Mutation - radiation effects; Signal Transduction - drug effects; Signal Transduction - genetics; Signal Transduction - radiation effects; Skin - drug effects; Skin - pathology; Skin - radiation effects; Skin Aging - drug effects; Skin Aging - genetics; Skin Aging - radiation effects; Skin Neoplasms - drug therapy; Skin Neoplasms - etiology; Skin Neoplasms - pathology; Transforming Growth Factor beta - antagonists & inhibitors; Transforming Growth Factor beta - metabolism; Tumor Escape - genetics; Tumor Escape - radiation effects; Tumor Microenvironment - drug effects; Tumor Microenvironment - genetics; Tumor Microenvironment - radiation effects; Ultraviolet Rays - adverse effects; Xenograft Model Antitumor Assays; BCC; FN; CAF; AK; EMT; TME; ECM; CTGF; SC; MMP; CSC; SCC; PI3K; SBE; KC; SK; pSMAD; wt; cSCC; HF
• ISSN: 0022-202X; 1523-1747; 1523-1747
• DOI: 10.1016/j.jid.2020.11.007

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.