Injury-Driven Stiffening of the Dermis Expedites Skin Carcinoma Progression
Injury-Driven Stiffening of the Dermis Expedites Skin Carcinoma Progression
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DOI：
10.1158/0008-5472.can-15-1348
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发表时间：
2016-02-15
期刊：
影响因子：
11.2
通讯作者：
Bruckner-Tuderman, Leena
中科院分区：
文献类型：
--
作者：
Mittapalli, Venugopal R.;Madl, Josef;Bruckner-Tuderman, Leena
隐性营养不良大疱性表皮松解症(RDEB)是一种遗传性皮肤脆性疾病，其特征是损伤导致水泡形成，进行性软组织纤维化，以及早期侵袭性皮肤鳞状细胞癌(CSCC)的高风险。然而，RDEB向CSCC异常快速进展的潜在机制尚不清楚。在这项研究中，我们利用RDEB的遗传模型和器官型皮肤培养，研究了损伤诱导的皮肤改变对CSCC发展的贡献。对RDEB患者样本的分析表明，癌前病变对真皮微环境的变化推动了肿瘤的进展，这导致我们使RDEB的VII型胶原亚型小鼠模型发生化学致癌。致癌物处理的RDEB小鼠发生了与人类RDEB-CSCC相似的侵袭性肿瘤，而野生型小鼠形成了乳头状瘤，这表明RDEB-CSCC的侵袭性与突变无关。RDEB真皮固有的结构不稳定性，再加上反复的损伤，增加了转化生长因子β的生物利用度，促进了细胞外基质的产生，交联化，真皮纤维增厚和组织硬化。生物物理改变的真皮增加了肿瘤细胞中的肌成纤维细胞活性和整合素β1/pFAK/PACK机械信号，进一步表明CSCC的进展是由RDEB组织微环境中预先存在的损伤驱动的变化所控制的。用转化生长因子β信号、赖氨酰氧化酶或整合素β1介导的机械信号转导的抑制剂处理三维器官型RDEB皮肤培养物可减少或绕过组织僵硬和有限的肿瘤细胞侵袭。总之，这些发现提供了一种新的机制，使RDEB组织变得恶性，并提供了新的可用药治疗的靶点，以防止CSCC的发生。(C)2015年AACR。
Recessive dystrophic epidermolysis bullosa (RDEB) is a genetic skin fragility disorder characterized by injury-driven blister formation, progressive soft-tissue fibrosis, and a highly elevated risk of early-onset aggressive cutaneous squamous cell carcinoma (cSCC). However, the mechanisms underlying the unusually rapid progression of RDEB to cSCC are unknown. In this study, we investigated the contribution of injury-induced skin alterations to cSCC development by using a genetic model of RDEB and organotypic skin cultures. Analysis of RDEB patient samples suggested that premalignant changes to the dermal microenvironment drive tumor progression, which led us to subject a collagen VII hypomorphic mouse model of RDEB to chemical carcinogenesis. Carcinogen- treated RDEB mice developed invasive tumors phenocopying human RDEB-cSCC, whereas wild-type mice formed papillomas, indicating that the aggressiveness of RDEB-cSCC is mutation-independent. The inherent structural instability of the RDEB dermis, combined with repeated injury, increased the bioavailability of TGF beta, which promoted extracellular matrix production, cross-linking, thickening of dermal fibrils, and tissue stiffening. The biophysically altered dermis increased myofibroblast activity and integrin beta 1/pFAK/pAKT mechanosignaling in tumor cells, further demonstrating that cSCC progression is governed by pre-existing injury-driven changes in the RDEB tissue microenvironment. Treatment of three-dimensional organotypic RDEB skin cultures with inhibitors of TGF beta signaling, lysyl oxidase, or integrin beta 1-mediated mechanosignaling reduced or bypassed tissue stiffness and limited tumor cell invasion. Collectively, these findings provide a new mechanism by which RDEB tissue becomes malignant and offer new druggable therapeutic targets to prevent cSCC onset. (C) 2015 AACR.