TEM1/endosialin 在人类和鼠类脑肿瘤中的特征分析。
Characterization of TEM1/endosialin in human and murine brain tumors.
机构信息
Department of Neurosurgery, The University of Rochester, Rochester, NY, USA.
出版信息
BMC Cancer. 2009 Nov 30;9:417. doi: 10.1186/1471-2407-9-417.
BACKGROUND
TEM1/endosialin is an emerging microvascular marker of tumor angiogenesis. We characterized the expression pattern of TEM1/endosialin in astrocytic and metastatic brain tumors and investigated its role as a therapeutic target in human endothelial cells and mouse xenograft models.
METHODS
In situ hybridization (ISH), immunohistochemistry (IH) and immunofluorescence (IF) were used to localize TEM1/endosialin expression in grade II-IV astrocytomas and metastatic brain tumors on tissue microarrays. Changes in TEM1/endosialin expression in response to pro-angiogenic conditions were assessed in human endothelial cells grown in vitro. Intracranial U87MG glioblastoma (GBM) xenografts were analyzed in nude TEM1/endosialin knockout (KO) and wildtype (WT) mice.
RESULTS
TEM1/endosialin was upregulated in primary and metastatic human brain tumors, where it localized primarily to the tumor vasculature and a subset of tumor stromal cells. Analysis of 275 arrayed grade II-IV astrocytomas demonstrated TEM1/endosialin expression in 79% of tumors. Robust TEM1/endosialin expression occurred in 31% of glioblastomas (grade IV astroctyomas). TEM1/endosialin expression was inversely correlated with patient age. TEM1/endosialin showed limited co-localization with CD31, alphaSMA and fibronectin in clinical specimens. In vitro, TEM1/endosialin was upregulated in human endothelial cells cultured in matrigel. Vascular Tem1/endosialin was induced in intracranial U87MG GBM xenografts grown in mice. Tem1/endosialin KO vs WT mice demonstrated equivalent survival and tumor growth when implanted with intracranial GBM xenografts, although Tem1/endosialin KO tumors were significantly more vascular than the WT counterparts.
CONCLUSION
TEM1/endosialin was induced in the vasculature of high-grade brain tumors where its expression was inversely correlated with patient age. Although lack of TEM1/endosialin did not suppress growth of intracranial GBM xenografts, it did increase tumor vascularity. The cellular localization of TEM1/endosialin and its expression profile in primary and metastatic brain tumors support efforts to therapeutically target this protein, potentially via antibody mediated drug delivery strategies.
背景
TEM1/内皮唾液酸糖蛋白是肿瘤血管生成的新兴微血管标志物。我们对星形细胞瘤和转移性脑肿瘤中 TEM1/内皮唾液酸糖蛋白的表达模式进行了特征描述，并研究了其作为人类内皮细胞和小鼠异种移植模型治疗靶点的作用。
方法
通过原位杂交（ISH）、免疫组织化学（IH）和免疫荧光（IF），在组织微阵列上定位 II-IV 级星形细胞瘤和转移性脑肿瘤中的 TEM1/内皮唾液酸糖蛋白表达。在体外培养的人类内皮细胞中，评估 TEM1/内皮唾液酸糖蛋白表达对促血管生成条件的变化。分析裸鼠 TEM1/内皮唾液酸糖蛋白敲除（KO）和野生型（WT）异种移植的 U87MG 胶质母细胞瘤（GBM）颅内肿瘤。
结果
TEM1/内皮唾液酸糖蛋白在原发性和转移性人脑肿瘤中上调，主要定位于肿瘤血管和肿瘤基质细胞的亚群。对 275 个排列的 II-IV 级星形细胞瘤进行分析显示，79%的肿瘤存在 TEM1/内皮唾液酸糖蛋白表达。31%的胶质母细胞瘤（IV 级星形细胞瘤）中存在强烈的 TEM1/内皮唾液酸糖蛋白表达。TEM1/内皮唾液酸糖蛋白表达与患者年龄呈负相关。TEM1/内皮唾液酸糖蛋白在临床标本中与 CD31、alphaSMA 和纤维连接蛋白的共定位有限。在体外，在 Matrigel 中培养的人类内皮细胞中 TEM1/内皮唾液酸糖蛋白上调。在小鼠体内生长的颅内 U87MG GBM 异种移植中诱导血管 TEM1/内皮唾液酸糖蛋白。与颅内 GBM 异种移植相比，Tem1/内皮唾液酸糖蛋白 KO 与 WT 小鼠的生存和肿瘤生长相当，尽管 Tem1/内皮唾液酸糖蛋白 KO 肿瘤的血管明显多于 WT 肿瘤。
结论
TEM1/内皮唾液酸糖蛋白在高级别脑肿瘤的血管中被诱导，其表达与患者年龄呈负相关。尽管缺乏 TEM1/内皮唾液酸糖蛋白并未抑制颅内 GBM 异种移植的生长，但它确实增加了肿瘤的血管生成。TEM1/内皮唾液酸糖蛋白在原发性和转移性脑肿瘤中的细胞定位及其表达谱支持通过抗体介导的药物输送策略来治疗该蛋白的努力。
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