犬原发性脑肿瘤中尿激酶型纤溶酶原激活物系统的表达与活性
Expression and activity of the urokinase plasminogen activator system in canine primary brain tumors.
作者信息
Rossmeisl John H, Hall-Manning Kelli, Robertson John L, King Jamie N, Davalos Rafael V, Debinski Waldemar, Elankumaran Subbiah
机构信息
Veterinary and Comparative Neuro-Oncology Laboratory.
Department of Small Animal Clinical Sciences.
出版信息
Onco Targets Ther. 2017 Apr 12;10:2077-2085. doi: 10.2147/OTT.S132964. eCollection 2017.
BACKGROUND
The expression of the urokinase plasminogen activator receptor (uPAR), a glycosylphosphatidylinositol-anchored protein family member, and the activity of its ligand, urokinase-type plasminogen activator (uPA), have been associated with the invasive and metastatic potentials of a variety of human brain tumors through their regulation of extracellular matrix degradation. Domesticated dogs develop naturally occurring brain tumors that share many clinical, phenotypic, molecular, and genetic features with their human counterparts, which has prompted the use of the dogs with spontaneous brain tumors as models to expedite the translation of novel brain tumor therapeutics to humans. There is currently little known regarding the role of the uPA system in canine brain tumorigenesis. The objective of this study was to characterize the expression of uPAR and the activity of uPA in canine brain tumors as justification for the development of uPAR-targeted brain tumor therapeutics in dogs.
METHODS
We investigated the expression of uPAR in 37 primary canine brain tumors using immunohistochemistry, Western blotting, real-time quantitative polymerase chain reaction analyses, and by the assay of the activity of uPA using casein-plasminogen zymography.
RESULTS
Expression of uPAR was observed in multiple tumoral microenvironmental niches, including neoplastic cells, stroma, and the vasculature of canine brain tumors. Relative to normal brain tissues, uPAR protein and mRNA expression were significantly greater in canine meningiomas, gliomas, and choroid plexus tumors. Increased activity of uPA was documented in all tumor types.
CONCLUSIONS
uPAR is overexpressed and uPA activity increased in canine meningiomas, gliomas, and choroid plexus tumors. This study illustrates the potential of uPAR/uPA molecularly targeted approaches for canine brain tumor therapeutics and reinforces the translational significance of canines with spontaneous brain tumors as models for human disease.
背景
尿激酶型纤溶酶原激活物受体（uPAR）是一种糖基磷脂酰肌醇锚定蛋白家族成员，其表达及其配体尿激酶型纤溶酶原激活物（uPA）的活性，通过对细胞外基质降解的调控，与多种人类脑肿瘤的侵袭和转移潜能相关。家养犬会自然发生脑肿瘤，这些肿瘤在临床、表型、分子和遗传特征上与人类脑肿瘤有许多相似之处，这促使人们将患有自发性脑肿瘤的犬用作模型，以加速新型脑肿瘤治疗方法向人类的转化。目前对于uPA系统在犬脑肿瘤发生中的作用知之甚少。本研究的目的是表征犬脑肿瘤中uPAR的表达和uPA的活性，为开发针对犬的uPAR靶向脑肿瘤治疗方法提供依据。
方法
我们使用免疫组织化学、蛋白质印迹、实时定量聚合酶链反应分析，对37例原发性犬脑肿瘤中uPAR的表达进行了研究，并通过酪蛋白-纤溶酶原酶谱法检测uPA的活性。
结果
在犬脑肿瘤的多个肿瘤微环境龛中观察到uPAR的表达，包括肿瘤细胞、基质和脉管系统。相对于正常脑组织，uPAR蛋白和mRNA表达在犬脑膜瘤、胶质瘤和脉络丛肿瘤中显著更高。在所有肿瘤类型中均记录到uPA活性增加。
结论
uPAR在犬脑膜瘤、胶质瘤和脉络丛肿瘤中过表达，uPA活性增加。本研究阐明了uPAR/uPA分子靶向方法用于犬脑肿瘤治疗的潜力，并强化了患有自发性脑肿瘤的犬作为人类疾病模型的转化意义。
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