Stem Cell Institute, University of Minnesota, Minneapolis, MN, USA.
Department of Pediatrics, Blood and Marrow Transplantation, University of Minnesota, Minneapolis, MN, USA.
Exp Dermatol. 2021 May;30(5):664-675. doi: 10.1111/exd.14304. Epub 2021 Feb 28.
Squamous cell carcinoma (SCC) develops in more than 80% of individuals with the skin blistering disorder recessive dystrophic epidermolysis bullosa (RDEB). In contrast with UV-induced SCC, RDEB-SCC results from skin damage and has a high proliferative and metastatic rate with 5-year survival near zero. Our objective is to determine the mechanisms underlying the increased metastatic tendencies of RDEB-SCC. RDEB-SCC cultured cell lines were treated with RDEB and non-RDEB fibroblast conditioned media and assayed for migration and invasion with and without small molecule inhibitors for TGFβ and other downstream signal transduction pathways. TGFβ1 secreted by RDEB dermal fibroblasts has been found to induce migration and invasion and to increase expression of epithelial-to-mesenchymal transition markers in an RDEB-SCC line. These effects were reversed upon inhibition of TGFβ signalling and its downstream pathways MEK/ERK, P38 kinase and SMAD3. A number of small molecule inhibitors for these pathways are in different phases of various clinical trials and may be applicable to RDEB-SCC patients. Studying the mechanisms of the extreme form RDEB-SCC may inform studies of other types of SCC, as well as lead to better therapies for RDEB patients.
鳞状细胞癌（SCC）在超过 80%的隐性营养不良性大疱性表皮松解症（RDEB）皮肤水疱病患者中发展。与 UV 诱导的 SCC 不同，RDEB-SCC 是由皮肤损伤引起的，具有高增殖和转移率，5 年生存率接近零。我们的目标是确定 RDEB-SCC 转移趋势增加的机制。用 RDEB 和非 RDEB 成纤维细胞条件培养基处理 RDEB-SCC 培养细胞系，并在有和没有 TGFβ和其他下游信号转导途径的小分子抑制剂的情况下检测迁移和侵袭。已经发现 RDEB 真皮成纤维细胞分泌的 TGFβ1 诱导 RDEB-SCC 系的迁移和侵袭，并增加上皮-间充质转化标志物的表达。这些效应在 TGFβ信号及其下游途径 MEK/ERK、P38 激酶和 SMAD3 被抑制时被逆转。这些途径的许多小分子抑制剂处于不同的临床试验阶段，可能适用于 RDEB-SCC 患者。研究 RDEB-SCC 的极端形式的机制可能会为其他类型的 SCC 研究提供信息，并为 RDEB 患者提供更好的治疗方法。
