Expression of CD163 prevents apoptosis through the production of granulocyte colony-stimulating factor in meningioma

CD163 is a 130-kDa transmembrane protein expressed in human monocytes and macrophages that was initially identified as RM3/1 by Zwadlo et al in 1987.1 Previously, expression of CD163 was thought to be restricted to monocytes, macrophages, and neoplasms associated with monocyte/macrophage lineage.2 In fact, CD163 is widely used as an immunohistochemical marker of monocytes and macrophages in routine pathological diagnosis. The molecular function of CD163 includes internalization of hemoglobin-haptoglobin complexes, an erythroblast adhesion receptor, a receptor for tumor necrosis factor-like weak inducer of apoptosis (TWEAK), and a receptor for distinct pathogens.3–8 In addition, CD163 is also attracting attention as a marker of tumor-associated macrophage (TAM), which is associated with a worse prognosis in many cancers.9–11 Moreover, recent analyses have revealed that the tumor cell itself in breast, rectal, and bladder cancer expressed CD163 and that CD163 expression in each of the tumor cells was associated with poor prognosis,12–14 suggesting the novel function of CD163 associated with tumor progression. Meningioma is one of the most common intracranial tumors in adults and accounts for 20%–32% of total intracranial tumors.15,16 According to the World Health Organization (WHO) classification (2007), meningiomas are histologically classified into grade I, II, and III.17 About 90% of meningiomas correspond to grade I, benign tumor; however, ∼10% are classified as grade II or III, exhibiting an unfavorable clinical course,16 although it has been recently reported that atypical meningioma occupied up to 20% of meningiomas with use of the latest WHO classification,17 in which meningioma with increased mitotic activity or ≥3 of the following histological features, including hypercellularity, macronucleoli, small cell formation, patternless architecture, and necrosis, is defined as atypical meningioma (grade II). Grade II and III meningiomas represent a risk of recurrence of 30%–40% and 50%–80%, respectively, after surgical resection,19 and the 5-year survival rates among patients with grade II and III meningiomas were 67.5% and 60%, respectively.18 In addition, even benign meningioma of grade I sometimes shows recurrence and/or malignant progression.19,20 The therapeutic modality to high-grade meningioma includes surgical resection, preoperative embolization, adjuvant radiotherapy, and multidrug chemotherapy. There have been also some trials and retrospective reports on targeted molecular therapies, including gefitinib, erlotinib, imatinib, and bevacizumab.21–25 However, the treatment efficacy, especially of chemotherapy, was limited, and there is currently no standardized treatment for recurrent high-grade meningiomas after surgery and radiation therapy. Thus, the proper diagnosis of high-grade meningioma based on reliable molecular markers is requested to the neuropathologists, and the management of high-grade meningioma and recurrent benign meningioma is a clinically significant theme for neurosurgeons. Before starting this study, we were aware that CD163 is expressed in a subset of high-grade meningioma during the process of differential diagnosis to histiocytic tumors. Here, we analyzed the correlation of CD163 expression in meningioma and pathological atypical features. Moreover, we also examined the molecular function of CD163 in vitro and in vivo with use of meningioma cell lines, including primary culture cells derived from surgically resected meningioma specimens, and elucidated the novel mechanism of CD163 to promote tumor growth by preventing apoptosis.