Increased Vascular Adhesion Protein 1 (VAP-1) Levels are Associated with Alternative M2 Macrophage Activation and Poor Prognosis for Human Gliomas

Shu-Jyuan Chang; Hung-Pin Tu; Yen-Chang Clark Lai; Chi-Wen Luo; Takahide Nejo; Shota Tanaka; Chee-Yin Chai; Aij-Lie Kwan

doi:10.3390/diagnostics10050256

Increased Vascular Adhesion Protein 1 (VAP-1) Levels are Associated with Alternative M2 Macrophage Activation and Poor Prognosis for Human Gliomas

Diagnostics (Basel). 2020 Apr 27;10(5):256. doi: 10.3390/diagnostics10050256.

Authors

Shu-Jyuan Chang¹, Hung-Pin Tu², Yen-Chang Clark Lai³, Chi-Wen Luo^{4

5}, Takahide Nejo⁶, Shota Tanaka⁶, Chee-Yin Chai^{3

7

8}, Aij-Lie Kwan^{9

10}

Affiliations

¹ Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.
² Department of Public Health and Environmental Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.
³ Department of Pathology, Kaohsiung Medical University Chung Ho Memorial Hospital, Kaohsiung 80756, Taiwan.
⁴ Division of Breast Surgery, Department of Surgery, Kaohsiung Medical University Chung Ho Memorial Hospital, Kaohsiung 80756, Taiwan.
⁵ Department of Surgery, Kaohsiung Medical University Chung Ho Memorial Hospital, Kaohsiung 80756, Taiwan..
⁶ Department of Neurosurgery, Graduate School of Medicine, University of Tokyo, Tokyo 113-0033, Japan.
⁷ Department of Pathology, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.
⁸ Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 80424, Taiwan.
⁹ Department of Neurosurgery, Kaohsiung Medical University Chung Ho Memorial Hospital, Kaohsiung 80756, Taiwan.
¹⁰ Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.

Abstract

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 AOC3 (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 (p = 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 (p < 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 (p < 0.0001). Multivariate analysis indicated that VAP-1 alone and co-expressed with CD163 were the significantly independent indicators (both p < 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.

Keywords: M2 macrophage activation; human gliomas; poor prognosis; vascular adhesion protein 1.