Zalles Michelle, Smith Nataliya, Saunders Debra, Guzman Mayra, Lerner Megan, Fung Kar-Ming, Babu Anish, Battiste James, Chung Junho, Hwang Kyusang, Jin Junyeong, Towner Rheal A
Advanced Magnetic Resonance Center, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA.
Oklahoma Center for Neuroscience, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
Neurooncol Adv. 2021 Sep 17;3(1):vdab132. doi: 10.1093/noajnl/vdab132. eCollection 2021 Jan-Dec.
Glioblastoma (GBM) is the most aggressive malignant primary brain tumor in adults. These high-grade gliomas undergo unregulated vascular angiogenesis, migration and cell proliferation allowing the tumor cells to evade cell-cycle checkpoints and apoptotic pathways. The Epidermal growth factor, latrophilin, and seven transmembrane domain-containing 1 on chromosome 1 (ELTD1) is an angiogenic biomarker that is highly expressed in malignant gliomas. Novel treatments targeting ELTD1 with monovalent monoclonal (mmAb) and single chain variable fragment (scFv) antibodies were effective in increasing animal survival, decreasing tumor volume and normalizing the vasculature. Due to the success of our antibody treatments on angiogenesis, this study sought to determine if our anti-ELTD1 treatments affected other aspects of tumorigenesis (cell proliferation, migration, and apoptosis) in a G55 glioma xenograft preclinical mouse model.
Tumor tissue from untreated, mmAb and scFv anti-ELTD1 treated animals was used to quantify the positivity levels of human mitochondrial antibody, c-MET and Ki-67 for cellular proliferation, migratory markers CD44v6, TRPM8, and BMP2, and cleaved caspase 3 to assess apoptotic activity.
This approach demonstrated that our anti-ELTD1 treatments directly affected and decreased the human tumor cells within the tumor region. Additionally, there was a significant decrease in both cellular proliferation and migration due to anti-ETLD1 therapy. Lastly, anti-ELTD1 treatments successfully increased apoptotic activity within the tumor region.
Our data suggest that anti-ELTD1 therapies would be effective against malignant gliomas by having a multi-focal effect and targeting all four aspects of tumorigenesis.
胶质母细胞瘤（GBM）是成人中最具侵袭性的恶性原发性脑肿瘤。这些高级别胶质瘤经历不受调控的血管生成、迁移和细胞增殖，使肿瘤细胞能够逃避细胞周期检查点和凋亡途径。1号染色体上的表皮生长因子、亲嗜素和含七个跨膜结构域1（ELTD1）是一种血管生成生物标志物，在恶性胶质瘤中高度表达。用单价单克隆（mmAb）和单链可变片段（scFv）抗体靶向ELTD1的新型治疗方法在提高动物存活率、减小肿瘤体积和使脉管系统正常化方面是有效的。由于我们的抗体治疗在血管生成方面取得成功，本研究旨在确定我们的抗ELTD1治疗是否会影响G55胶质瘤异种移植临床前小鼠模型中肿瘤发生的其他方面（细胞增殖、迁移和凋亡）。
来自未治疗、mmAb和scFv抗ELTD1治疗动物的肿瘤组织用于量化人线粒体抗体、c-MET和Ki-67的阳性水平，以评估细胞增殖、迁移标志物CD44v6、TRPM8和BMP2，以及裂解的半胱天冬酶3以评估凋亡活性。
该方法表明，我们的抗ELTD1治疗直接影响并减少了肿瘤区域内的人肿瘤细胞。此外，抗ETLD1治疗导致细胞增殖和迁移均显著减少。最后，抗ELTD1治疗成功增加了肿瘤区域内的凋亡活性。
我们的数据表明，抗ELTD1疗法通过具有多焦点效应并靶向肿瘤发生的所有四个方面，对恶性胶质瘤有效。
