Expression and activity of the urokinase plasminogen activator system in canine primary brain tumors.
Expression and activity of the urokinase plasminogen activator system in canine primary brain tumors.
复制标题
DOI：
10.2147/ott.s132964
复制
发表时间：
2017
影响因子：
4
通讯作者：
Elankumaran S
中科院分区：
文献类型：
--
作者：
Rossmeisl JH;Hall-Manning K;Robertson JL;King JN;Davalos RV;Debinski W;Elankumaran S
尿激酶纤溶酶原激活剂受体（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剂（uPA）的活性通过调节细胞外基质降解与多种人类脑肿瘤的侵袭和转移潜力相关。驯化的狗会自然产生脑瘤，这些脑瘤在临床、表型、分子和遗传上与人类的脑瘤有许多共同的特征，这促使人们将患有自发性脑瘤的狗作为模型，以加快新的脑瘤治疗方法对人类的转化。目前对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uPAR靶向的犬脑肿瘤治疗药物提供依据。我们采用免疫组织化学、Western blotting、实时定量聚合酶链反应分析和酪蛋白-纤溶酶原酶谱法检测uPA的活性，研究了uPAR在37例原发性犬脑肿瘤中的表达。uPAR在犬脑肿瘤的肿瘤细胞、间质和血管等多个肿瘤微环境中均有表达。与正常脑组织相比，犬脑膜瘤、胶质瘤和脉络膜丛肿瘤中uPAR蛋白和mRNA的表达显著增加。uPA活性在所有肿瘤类型中均有升高。uPAR在犬脑膜瘤、胶质瘤和脉络膜丛肿瘤中过表达且uPA活性升高。这项研究说明了uPAR/uPA分子靶向方法在犬脑肿瘤治疗中的潜力，并加强了犬自发性脑肿瘤作为人类疾病模型的翻译意义。
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. 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. 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. 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.