Chang Shu-Jyuan, Tu Hung-Pin, Lai Yen-Chang Clark, Luo Chi-Wen, Nejo Takahide, Tanaka Shota, Chai Chee-Yin, Kwan Aij-Lie
Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.
Department of Public Health and Environmental Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.
Diagnostics (Basel). 2020 Apr 27;10(5):256. doi: 10.3390/diagnostics10050256.
Glioma is characterized by a high heterogeneity in the brain tumor. Abundant tumor-associated macrophages (TAMs) exist as neoplastic tissues, implicating tumor plasticity and thus leading to therapeutic challenges. Vascular adhesion protein (VAP-1) potentially serves as a mediator for TAM immunity in tumor milieu. We previously demonstrated that VAP-1 could contribute to tumor malignancy, but its characteristics in TAM immunity of glioma progression are still unclear. This study explored the association of VAP-1 expression with TAM distribution as well as the resulting clinical significance and prognostic value in human gliomas. An in-depth analysis of (VAP-1) gene expression was performed using 695 glioma samples derived from the cancer genome atlas (TCGA)-lower grade glioma and glioblastoma (GBMLGG) cohort. Bioinformatic analysis confirmed that VAP-1 expression is associated with poor prognosis of glioma patients ( = 0.0283). VAP-1 and TAM biomarkers (CD68, iNOS, and CD163) were evaluated by immunohistochemistry in 108 gliomas from Kaohsiung Medical University Hospital. VAP-1+ was expressed in 56 (51.85%) cases and this phenotype revealed a significant association with overall survival in Kaplan-Meier analysis ( < 0.0001). Immunohistochemical double staining showed that VAP-1 immunoreactivity was present around CD163+ M2 infiltration location, including aggressive lesions and neighboring neovasculature. We demonstrated that high VAP-1 expression levels positively correlated with CD163+ M2 activation and coexpression of these two proteins was associated with worse survival in gliomas ( < 0.0001). Multivariate analysis indicated that VAP-1 alone and co-expressed with CD163 were the significantly independent indicators (both < 0.0001). Furthermore, VAP-1/CD163 coexpression exhibited excellent diagnostic accuracy in gliomas (AUC = 0.8008). In conclusion, VAP-1 and TAM CD163 M2 coexpression was found in glioma tissues belonging to a highly malignant subgroup that was associated with poor prognosis. These results implied VAP-1 abundance is closely linked to alternative M2 activation during glioma progression. From the aforementioned data, a reasonable inference is that VAP-1 combined with targeting M2 immunity might be an effective therapeutic target for human gliomas.
胶质瘤的特点是在脑肿瘤中具有高度异质性。大量肿瘤相关巨噬细胞（TAM）作为肿瘤组织存在，这意味着肿瘤具有可塑性，从而带来治疗挑战。血管粘附蛋白（VAP-1）可能作为肿瘤微环境中TAM免疫的介质。我们之前证明VAP-1可能促成肿瘤恶性进展，但其在胶质瘤进展的TAM免疫中的特征仍不清楚。本研究探讨了VAP-1表达与TAM分布的关联以及其在人类胶质瘤中的临床意义和预后价值。使用来自癌症基因组图谱（TCGA）-低级别胶质瘤和胶质母细胞瘤（GBMLGG）队列的695个胶质瘤样本对（VAP-1）基因表达进行了深入分析。生物信息学分析证实VAP-1表达与胶质瘤患者的不良预后相关（=0.0283）。通过免疫组织化学对高雄医学大学医院的108例胶质瘤中的VAP-1和TAM生物标志物（CD68、诱导型一氧化氮合酶和CD163）进行了评估。56例（51.85%）病例中表达VAP-1+，在Kaplan-Meier分析中这种表型与总生存期显著相关（<0.0001）。免疫组织化学双重染色显示VAP-1免疫反应性存在于CD163+ M2浸润部位周围，包括侵袭性病变和邻近的新血管。我们证明高VAP-1表达水平与CD163+ M2活化呈正相关，这两种蛋白的共表达与胶质瘤患者较差的生存率相关（<0.0001）。多变量分析表明单独的VAP-1以及与CD163共表达均为显著的独立指标（均<0.0001）。此外，VAP-1/CD163共表达在胶质瘤中表现出优异的诊断准确性（AUC = 0.8008）。总之，在属于高度恶性亚组的胶质瘤组织中发现了VAP-1与TAM CD163 M2共表达，这与不良预后相关。这些结果表明VAP-1丰度与胶质瘤进展过程中的替代性M2活化密切相关。根据上述数据，合理推断是VAP-与靶向M2免疫相结合可能是人类胶质瘤的有效治疗靶点。
