TGFβ Signaling in Photoaging and UV-Induced Skin Cancer.
TGFβ Signaling in Photoaging and UV-Induced Skin Cancer.
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DOI：
10.1016/j.jid.2020.11.007
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发表时间：
2021-04
期刊：
影响因子：
--
通讯作者：
Wang XJ
中科院分区：
文献类型：
--
作者：
Ke Y;Wang XJ
紫外线（UV）辐射是导致光老化和UV诱导的皮肤癌的皮肤过早老化的主要病因。在皮肤中，TGFβ信号传导是角质形成细胞的生长抑制剂和真皮中的促纤维化因子。它对肿瘤进展产生背景依赖性影响。慢性紫外线暴露可能导致TGFβ1/Smad 3信号转导激活，并有助于金属蛋白酶诱导的胶原降解和光老化中的光炎症。紫外线照射也会导致TGFβ途径关键元件的基因突变，包括TGFβRI、TGFβRII、Smad 2和Smad 4。这些突变使肿瘤细胞能够逃避TGFβ诱导的生长抑制，并诱导基因组不稳定性和癌症干细胞，导致皮肤鳞状细胞癌（cSCC）的发生、进展、侵袭和转移。此外，UV诱导的突变导致cSCC、基底细胞癌（BCC）和皮肤黑色素瘤的肿瘤微环境（TME）中TGFβ过表达，导致炎症、血管生成、癌症相关成纤维细胞和免疫抑制，支持癌症存活、免疫逃避和转移。TGFβ的多效性作用为光老化和皮肤癌提供了可能的治疗选择。鉴于在cSCC、BCC和皮肤黑色素瘤中观察到的高UV诱导的突变负荷和免疫抑制性TME，用TGFβ信号传导抑制剂和免疫检查点阻断的组合治疗可以逆转免疫逃避以减少肿瘤生长。
Ultraviolet (UV) radiation is a major etiology for premature skin aging that leads to photoaging and UV-induced skin cancers. In 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 photo-inflammation 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). Further, 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.
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