Cutaneous squamous cell carcinoma (cSCC) is the most common metastatic skin cancer and the metastatic disease is associated with poor prognosis. Cancer‐associated fibroblasts (CAFs) promote progression of cancer, but their role in cSCC is largely unknown. We examined the potential of CAF markers in the assessment of metastasis risk and prognosis of primary cSCC. We utilized multiplexed fluorescence immunohistochemistry for profiling CAF landscape in metastatic and non‐metastatic primary human cSCCs, in metastases, and in premalignant epidermal lesions. Quantitative high‐resolution image analysis was performed with two separate panels of antibodies for CAF markers and results were correlated with clinical and histopathological parameters including disease‐specific mortality. Increased stromal expression of fibroblast activation protein (FAP), α‐smooth muscle actin, and secreted protein acidic and rich in cysteine (SPARC) were associated with progression to invasive cSCC. Elevation of FAP and platelet‐derived growth factor receptor‐β (PDGFRβ) expression was associated with metastasis risk of primary cSCCs. High expression of PDGFRβ and periostin correlated with poor prognosis. Multimarker combination defined CAF subset, PDGFRα−/PDGFRβ+/FAP+, was associated with invasion and metastasis, and independently predicted poor disease‐specific survival. These results identify high PDGFRβ expression alone and multimarker combination PDGFRα−/PDGFRβ+/FAP+ by CAFs as potential biomarkers for risk of metastasis and poor prognosis.

中文翻译：

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癌症相关成纤维细胞激活预测皮肤鳞状细胞癌的进展、转移和预后

皮肤鳞状细胞癌（cSCC）是最常见的转移性皮肤癌，转移性疾病与不良预后相关。癌症相关成纤维细胞 (CAF) 促进癌症进展，但它们在 cSCC 中的作用很大程度上未知。我们研究了 CAF 标记物在评估原发性鳞状细胞癌转移风险和预后方面的潜力。我们利用多重荧光免疫组织化学分析转移性和非转移性原发性人类 cSCC、转移瘤和癌前表皮病变中的 CAF 景观。使用两个独立的 CAF 标记物抗体组进行定量高分辨率图像分析，结果与临床和组织病理学参数（包括疾病特异性死亡率）相关。成纤维细胞激活蛋白 (FAP)、α-平滑肌肌动蛋白和富含半胱氨酸的酸性分泌蛋白 (SPARC) 的基质表达增加与侵袭性 cSCC 的进展相关。 FAP 和血小板衍生生长因子受体-β (PDGFRβ) 表达的升高与原发性 cSCC 的转移风险相关。 PDGFRβ和骨膜素的高表达与不良预后相关。多标志物组合定义的 CAF 子集 PDGFRα−/PDGFRβ+/FAP+ 与侵袭和转移相关，并独立预测较差的疾病特异性生存。这些结果将单独的高 PDGFRβ 表达和 CAF 的多标志物组合 PDGFRα−/PDGFRβ+/FAP+ 确定为转移风险和不良预后的潜在生物标志物。