Department of Dermatology and Venereology, Hôpital de Beaumont, Lausanne University Hospital Center, Lausanne, Switzerland; Program in Epithelial Biology and Department of Dermatology, Stanford University School of Medicine, Stanford, California, USA.
Department of Dermatology and Venereology, Hôpital de Beaumont, Lausanne University Hospital Center, Lausanne, Switzerland.
J Invest Dermatol. 2018 Nov;138(11):2432-2442. doi: 10.1016/j.jid.2018.04.029. Epub 2018 Jul 14.
Basal cell carcinoma (BCC) is the most frequent human cancer and is becoming an important health problem in an aging population. Based on their clinical and histological characteristics, thick BCC are typically divided into low-risk nodular and high-risk infiltrative subtypes, although the underlying mechanisms are poorly understood. We have identified molecular mechanisms that explain the aggressiveness of high-risk infiltrative BCC, with a potential direct clinical impact. In this study, we first show that fibroblasts, transforming growth factor-β, and fibronectin are found preferentially in infiltrative human BCC. This allowed us to develop in vivo models for the study of infiltrative BCC, which in turn let us confirm the role of transforming growth factor-β in inducing peritumoral fibronectin deposition and tumor infiltration. We then show that fibronectin promotes adhesion and migration of BCC cell lines through integrin α5β1-mediated phosphorylation of focal adhesion kinase. Fittingly, both inhibition of integrin α5β1 and phospho-focal adhesion kinase prevent fibronectin-induced migration of BCC cells in vitro as well as BCC infiltration in vivo. Altogether, our results open important insights into the pathogenesis of aggressive infiltrative BCC and identify integrin α5β1 or focal adhesion kinase inhibition as promising strategies for the treatment of advanced BCC.
基底细胞癌（BCC）是最常见的人类癌症，在人口老龄化的背景下，它正成为一个重要的健康问题。基于其临床和组织学特征，厚型 BCC 通常分为低风险结节型和高风险浸润型亚型，尽管其潜在机制仍不清楚。我们已经确定了可以解释高风险浸润性 BCC 侵袭性的分子机制，这可能具有直接的临床影响。在这项研究中，我们首先表明，成纤维细胞、转化生长因子-β 和纤维连接蛋白优先存在于浸润性人类 BCC 中。这使我们能够开发用于研究浸润性 BCC 的体内模型，进而证实转化生长因子-β在诱导肿瘤周围纤维连接蛋白沉积和肿瘤浸润中的作用。然后我们表明，纤维连接蛋白通过整合素 α5β1 介导的粘着斑激酶磷酸化促进 BCC 细胞系的黏附和迁移。恰当地，整合素 α5β1 和粘着斑激酶磷酸化的抑制均可阻止纤维连接蛋白诱导的 BCC 细胞在体外迁移以及 BCC 在体内浸润。总之，我们的研究结果为侵袭性浸润性 BCC 的发病机制提供了重要的见解，并确定了整合素 α5β1 或粘着斑激酶抑制作为治疗晚期 BCC 的有前途的策略。
