Department of Neurosurgery, University Hospital Frankfurt, 60528 Frankfurt am Main, Germany.
Department of Neurosurgery, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany.
Int J Mol Sci. 2022 Mar 13;23(6):3108. doi: 10.3390/ijms23063108.
Despite intensive research, glioblastoma remains almost invariably fatal. Various promising drugs targeting specific aspects of glioma biology, in addition to or as an alternative to antiproliferative chemotherapy, were not successful in larger clinical trials. Further insights into the biology of glioma and the mechanisms behind the evasive-adaptive response to targeted therapies is needed to help identify new therapeutic targets, prognostics, or predictive biomarkers. As a modulator of the canonically oncogenic Rho-GTPase pathway, Lipid phosphate phosphatase-related protein type 5 (LPPR5) is pivotal in influencing growth, angiogenesis, and therapeutic resistance. We used a GL261 murine orthotopic allograft glioma model to quantify the tumor growth and to obtain tissue for histological and molecular analysis. Epicortical intravital epi-illumination fluorescence video microscopy of the tumor cell spheroids was used to characterize the neovascular architecture and hemodynamics. GL261-glioma growth was delayed and decelerated after LPPR5 overexpression (LPPR5). We observed increased tumor cell apoptosis and decreased expression and secretion of vascular endothelial growth factor A in LPPR5 glioma. Hence, an altered micro-angioarchitecture consisting of dysfunctional small blood vessels was discovered in the LPPR5 tumors. Sunitinib therapy eliminated these vessels but had no effect on tumor growth or apoptosis. In general, LPPR5 overexpression generated a more benign, proapoptotic glioma phenotype with delayed growth and a dysfunctional vascular architecture.
尽管进行了深入研究，但胶质母细胞瘤仍然几乎总是致命的。除了抗增殖化疗之外，针对神经胶质瘤生物学特定方面的各种有前途的药物，或者作为其替代物，在更大的临床试验中都没有成功。需要进一步深入了解神经胶质瘤的生物学以及针对靶向治疗的逃避适应反应的机制，以帮助确定新的治疗靶点、预后或预测生物标志物。作为经典致癌性 Rho-GTPase 途径的调节剂，脂质磷酸酶相关蛋白 5（LPPR5）在影响生长、血管生成和治疗抵抗方面起着关键作用。我们使用 GL261 鼠原位同种异体神经胶质瘤移植模型来量化肿瘤生长并获得组织进行组织学和分子分析。肿瘤细胞球体的皮层内活体荧光视频显微镜用于表征新生血管结构和血液动力学。过表达 LPPR5（LPPR5）后，GL261 神经胶质瘤的生长被延迟和减缓。我们观察到 LPPR5 神经胶质瘤中肿瘤细胞凋亡增加，血管内皮生长因子 A 的表达和分泌减少。因此，在 LPPR5 肿瘤中发现了一种由功能失调的小血管组成的改变的微血管结构。舒尼替尼治疗消除了这些血管，但对肿瘤生长或凋亡没有影响。总的来说，LPPR5 过表达产生了更良性、促凋亡的神经胶质瘤表型，其生长延迟且血管结构功能失调。
