Laboratory of Cutaneous Physiopathology and Integrated Center of Metabolomics Research, San Gallicano Dermatologic Institute, IRCCS, 00100 Rome, Italy.
Oncologic and Preventative Dermatology, San Gallicano Dermatological Institute, IRCCS, 00100 Rome, Italy.
Int J Mol Sci. 2020 Jan 22;21(3):720. doi: 10.3390/ijms21030720.
Nevoid basal cell carcinoma syndrome (NBCCS), also named Gorlin syndrome, is a rare multisystem genetic disorder characterized by marked predisposition to basal cell carcinomas (BCCs), childhood medulloblastomas, maxillary keratocysts, celebral calcifications, in addition to various skeletal and soft tissue developmental abnormalities. Mutations in the tumor suppressor gene () have been found to be associated in the majority of NBCCS cases. somatic mutations and loss of heterozygosity are also very frequent in sporadic BCCs. Unlike non-syndromic patients, NBCCS patients develop multiple BCCs in sun-protected skin area starting from early adulthood. Recent studies suggest that dermo/epidermal interaction could be implicated in BCC predisposition. According to this idea, NBCCS fibroblasts, sharing with keratinocytes the same germline mutation and consequent constitutive activation of the Hh pathway, display features of carcinoma-associated fibroblasts (CAF). This phenotypic traits include the overexpression of growth factors, specific microRNAs profile, modification of extracellular matrix and basement membrane composition, increased cytokines and pro-angiogenic factors secretion, and a complex alteration of the Wnt/-catenin pathway. Here, we review studies about the involvement of dermal fibroblasts in BCC predisposition of Gorlin syndrome patients. Further, we matched the emerged NBCCS fibroblast profile to those of CAF to compare the impact of cell autonomous "pre-activated state" due to mutations to those of skin tumor stroma.
结节性硬化症相关的基底细胞癌综合征（NBCCS），也称 Gorlin 综合征，是一种罕见的多系统遗传性疾病，其特征为基底细胞癌（BCC）、儿童髓母细胞瘤、上颌角化囊肿、脑钙化的显著易感性，此外还有各种骨骼和软组织发育异常。大多数 NBCCS 病例中发现肿瘤抑制基因 （） 的突变与之相关。体细胞突变和杂合性丢失在散发性 BCC 中也非常频繁。与非综合征患者不同，NBCCS 患者从成年早期开始就在阳光保护的皮肤区域出现多发性 BCC。最近的研究表明，皮肤/表皮相互作用可能与 BCC 的易感性有关。根据这一观点，NBCCS 成纤维细胞与角质形成细胞共享相同的种系突变，并因此导致 Hh 通路的组成性激活，表现出癌相关成纤维细胞（CAF）的特征。这些表型特征包括生长因子的过度表达、特定的 microRNA 谱、细胞外基质和基底膜组成的改变、细胞因子和促血管生成因子分泌的增加，以及 Wnt/-连环蛋白通路的复杂改变。在这里，我们回顾了关于皮肤成纤维细胞在 Gorlin 综合征患者 BCC 易感性中的作用的研究。此外，我们将新兴的 NBCCS 成纤维细胞表型与 CAF 的表型进行匹配，以比较由于 突变导致的细胞自主“预激活状态”与皮肤肿瘤基质的影响。
