Park Cheol Keun, Jung Woo Hee, Koo Ja Seung
Department of Pathology, Severance Hospital, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 03722, South Korea.
Breast Cancer Res Treat. 2016 Aug;159(1):55-69. doi: 10.1007/s10549-016-3929-2. Epub 2016 Jul 28.
Cancer-associated fibroblasts (CAFs) are classified into various functional subtypes such as fibroblast activation protein-α (FAP-α), fibroblast specific protein-1 (FSP-1), platelet-derived growth factor receptor-α (PDGFR-α), and PDGFR-β. In this study, we compared the expression of CAF-related proteins in invasive lobular carcinoma (ILC) with those in invasive carcinoma of no special type (NST) and assessed the implications of the differences observed. Using tissue microarrays of 104 ILC and 524 invasive carcinoma (NST) cases, immunohistochemistry for CAF-related proteins [podoplanin, prolyl 4-hydroxylase, FAP-α, FSP-1/S100A4, PDGFR-α, PDGFR-β, and chondroitin sulfate proteoglycan (NG2)] was conducted. In invasive carcinoma (NST), tumor cells expressed a high level of PDGFR-α, whereas ILC tumor cells expressed high levels of podoplanin, prolyl 4-hydroxylase, FAP-α, and FSP-1/S100A4. In stromal cells of invasive carcinoma (NST), high expression levels of prolyl 4-hydroxylase, PDGFR-α, and NG2 were observed, whereas ILC stromal cells expressed high levels of FAP-α, FSP-1/S100A4, and PDGFR-β. In ILC, tumoral FSP-1/S100A4 positivity was associated with higher Ki-67 labeling index (p = 0.010) and non-luminal A type cancer (p = 0.014). Stromal PDGFR-α positivity was associated with lymph node metastasis (p = 0.011). On survival analysis of entire cases, tumoral FSP-1/S100A4 positivity (p = 0.002), stromal podoplanin positivity (p = 0.041), and stromal FSP-1/S100A4 negativity (p = 0.041) were associated with shorter disease-free survival; only tumoral FSP-1/S100A4 positivity (p = 0.044) was associated with shorter overall survival. In ILC, the expression of FAP-α and FSP-1/S100A4 was higher in both tumor and stromal cells than that observed in invasive carcinoma (NST). These results indicate that CAFs are a potential target in ILC treatment.
癌症相关成纤维细胞（CAFs）可分为多种功能亚型，如成纤维细胞活化蛋白-α（FAP-α）、成纤维细胞特异性蛋白-1（FSP-1）、血小板衍生生长因子受体-α（PDGFR-α）和血小板衍生生长因子受体-β（PDGFR-β）。在本研究中，我们比较了浸润性小叶癌（ILC）和成纤维细胞相关蛋白的表达与浸润性非特殊类型癌（NST）中的表达，并评估了观察到的差异的意义。使用104例ILC和524例浸润性癌（NST）病例的组织芯片，对CAF相关蛋白[血小板内皮细胞黏附分子、脯氨酰4-羟化酶、FAP-α、FSP-1/S100A4、PDGFR-α、PDGFR-β和硫酸软骨素蛋白聚糖（NG2）]进行免疫组织化学检测。在浸润性癌（NST）中，肿瘤细胞表达高水平的PDGFR-α，而ILC肿瘤细胞表达高水平的血小板内皮细胞黏附分子、脯氨酰4-羟化酶、FAP-α和FSP-1/S100A4。在浸润性癌（NST）的基质细胞中，观察到脯氨酰4-羟化酶、PDGFR-α和NG2的高表达水平，而ILC基质细胞表达高水平的FAP-α、FSP-1/S100A4和PDGFR-β。在ILC中，肿瘤FSP-1/S100A4阳性与较高的Ki-67标记指数（p = 0.010）和非腔A型癌症（p = 0.014）相关。基质PDGFR-α阳性与淋巴结转移相关（p = 0.011）。在对所有病例的生存分析中，肿瘤FSP-1/S100A4阳性（p = 0.002）、基质血小板内皮细胞黏附分子阳性（p = 0.041）和基质FSP-1/S100A4阴性（p = 0.041）与无病生存期较短相关；只有肿瘤FSP-1/S100A4阳性（p = 0.044）与总生存期较短相关。在ILC中，肿瘤和基质细胞中FAP-α和FSP-1/S100A4的表达均高于浸润性癌（NST）。这些结果表明，CAFs是ILC治疗中的一个潜在靶点。
