Department of Dermato-Venerology, Bispebjerg University Hospital, Bispebjerg Bakke 23, 2400, Copenhagen, Nordvest, Denmark.
Centre for GeoGenetics, Natural History Museum, University of Copenhagen, Copenhagen, Denmark.
BMC Cancer. 2017 Oct 7;17(1):675. doi: 10.1186/s12885-017-3663-0.
Cutaneous basal cell carcinoma (BCC) is the commonest cancer worldwide. BCC is locally invasive and the surrounding stromal microenvironment is pivotal for tumourigenesis. Cancer associated fibroblasts (CAFs) in the microenvironment are essential for tumour growth in a variety of neoplasms but their role in BCC is poorly understood.
Material included facial BCC and control skin from the peritumoural area and from the buttocks. With next-generation sequencing (NGS) we compared mRNA expression between BCC and peritumoural skin. qRT-PCR, immunohistochemical and immunofluorescent staining were performed to validate the NGS results and to investigate CAF-related cyto-and chemokines.
NGS revealed upregulation of 65 genes in BCC coding for extracellular matrix components pointing at CAF-related matrix remodeling. qRT-PCR showed increased mRNA expression of CAF markers FAP-α, PDGFR-β and prolyl-4-hydroxylase in BCC. Peritumoural skin (but not buttock skin) also exhibited high expression of PDGFR-β and prolyl-4-hydroxylase but not FAP-α. We found a similar pattern for the CAF-associated chemokines CCL17, CCL18, CCL22, CCL25, CXCL12 and IL6 with high expression in BCC and peritumoural skin but absence in buttock skin. Immunofluorescence revealed correlation between FAP-α and PDGFR-β and CXCL12 and CCL17.
Matrix remodeling is the most prominent molecular feature of BCC. CAFs are present within BCC stroma and associated with increased expression of chemokines involved in tumour progression and immunosuppression (CXCL12, CCL17). Fibroblasts from chronically sun-exposed skin near tumours show gene expression patterns resembling that of CAFs, indicating that stromal fibroblasts in cancer-free surgical BCC margins exhibit a tumour promoting phenotype.
皮肤基底细胞癌（BCC）是全球最常见的癌症。BCC 具有局部侵袭性，周围的基质微环境对肿瘤发生至关重要。肿瘤微环境中的癌症相关成纤维细胞（CAFs）在各种肿瘤的肿瘤生长中是必不可少的，但它们在 BCC 中的作用尚未得到充分了解。
本研究纳入了面部 BCC 及肿瘤旁和臀部正常皮肤组织。我们通过下一代测序（NGS）比较了 BCC 与肿瘤旁皮肤之间的 mRNA 表达。通过 qRT-PCR、免疫组化和免疫荧光染色验证 NGS 结果，并研究 CAF 相关细胞因子和趋化因子。
NGS 显示 BCC 中有 65 个基因上调，这些基因编码细胞外基质成分，提示与 CAF 相关的基质重塑。qRT-PCR 显示 BCC 中 CAF 标志物 FAP-α、PDGFR-β 和脯氨酰-4-羟化酶的 mRNA 表达增加。肿瘤旁皮肤（而非臀部皮肤）也表现出 PDGFR-β 和脯氨酰-4-羟化酶的高表达，但 FAP-α 不表达。我们发现 CAF 相关趋化因子 CCL17、CCL18、CCL22、CCL25、CXCL12 和 IL6 也存在类似的表达模式，即在 BCC 和肿瘤旁皮肤中高表达，而在臀部皮肤中不表达。免疫荧光显示 FAP-α 与 PDGFR-β 以及 CXCL12 与 CCL17 之间存在相关性。
基质重塑是 BCC 最显著的分子特征。CAFs 存在于 BCC 基质中，与参与肿瘤进展和免疫抑制的趋化因子（CXCL12、CCL17）表达增加有关。来自肿瘤附近慢性暴露于阳光皮肤的成纤维细胞表现出类似于 CAFs 的基因表达模式，这表明无肿瘤手术 BCC 边缘的基质成纤维细胞表现出促进肿瘤的表型。
