Abstract：
High-grade oligodendroglioma (HGOG) is the most common type of glioma in dogs and expresses platelet-derived growth factor receptor-α (PDGFR-α). Microvascular proliferation is often observed in HGOG. Therefore, the present study investigated the functional relationships between PDGFR-α, microvascular proliferation, and tumor cell proliferation in canine HGOG. The expression of PDGFR-α and PDGF-subunit A (PDGF-A) in tumor cells, as well as endothelial cells and pericytes of tumor-associated microvascular proliferations, in 45 canine HGOGs were examined immunohistochemically. Microvascular proliferation was observed in 24/45 cases (53%). PDGFR-α expression in tumor cells and microvascular proliferations was observed in 45/45 (100%) and 2/24 cases (8%), respectively. Furthermore, PDGF-A expression in tumor cells and microvascular proliferations was detected in 13/45 (29%) and 24/24 cases (100%), respectively. In vitro, stimulation of the canine HGOG cell line AOFB-01 with PDGF-A showed that the doubling time of AOFB-01 cells was significantly shorter with PDGF-A than without PDGF-A. Crenolanib (a PDGFR inhibitor) inhibited AOFB-01 cell proliferation. In vivo, the AOFB-01 xenograft mouse model was treated with crenolanib. Tumor xenografts were smaller in crenolanib-treated mice than in untreated control mice. PDGFR-α expression in tumor cells and PDGF-A expression in microvascular proliferations and tumor cells suggest autocrine and paracrine effects of PDGF-A in canine HGOG. The results of in vitro assays indicate that canine HGOG expresses functional PDGFR-α, which responds to PDGF-A. Therefore, PDGF-A produced by microvascular proliferations and tumor cells may promote the proliferation of PDGFR-α-expressing tumor cells in canine HGOG. PDGFR-α signaling has potential as a therapeutic target.
摘要：
高级少突胶质细胞瘤（HGOG）是狗中最常见的神经胶质瘤类型，表达血小板衍生生长因子受体-α（PDGFR-α）。在HGOG中经常观察到微血管增殖。因此,本研究调查了PDGFR-α，微血管增殖，和犬HGOG的肿瘤细胞增殖。PDGFR-α和PDGF-亚基A(PDGF-A)在肿瘤细胞中的表达,以及肿瘤相关微血管增殖的内皮细胞和周细胞，对45例犬HGOG进行了免疫组织化学检查。24/45例（53％）观察到微血管增殖。在45/45例(100%)和2/24例(8%)中观察到肿瘤细胞和微血管增殖中的PDGFR-α表达,分别。此外，在13/45例(29%)和24/24例(100%)中检测到PDGF-A在肿瘤细胞和微血管增殖中的表达,分别。体外，用PDGF-A刺激犬HGOG细胞系AOFB-01表明，使用PDGF-A的AOFB-01细胞的倍增时间明显短于不使用PDGF-A的AOFB-01细胞的倍增时间。Crenolanib(PDGFR抑制剂)抑制AOFB-01细胞增殖。在体内,AOFB-01异种移植小鼠模型用克诺拉尼处理。与未处理的对照小鼠相比,在克氏诺尼处理的小鼠中肿瘤异种移植物更小。PDGFR-α在肿瘤细胞中的表达和PDGF-A在微血管增殖和肿瘤细胞中的表达表明PDGF-A在犬HGOG中的自分泌和旁分泌作用。体外测定结果表明犬HGOG表达功能性PDGFR-α,对PDGF-A有反应因此,微血管增殖和肿瘤细胞产生的PDGF-A可能促进犬HGOG中表达PDGFR-α的肿瘤细胞的增殖。PDGFR-α信号传导具有作为治疗靶标的潜力。
