A Novel Molecular Diagnostic of Glioblastomas: Detection of an Extracellular Fragment of Protein Tyrosine Phosphatase μ
A Novel Molecular Diagnostic of Glioblastomas: Detection of an Extracellular Fragment of Protein Tyrosine Phosphatase μ
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DOI：
10.1593/neo.91940
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发表时间：
2010-04-01
期刊：
影响因子：
4.8
通讯作者：
Brady-Kalnay, Susann M.
中科院分区：
文献类型：
--
作者：
Burden-Gulley, Susan M.;Gates, Theresa J.;Brady-Kalnay, Susann M.
我们最近发现正常人脑和低级别星形细胞瘤表达受体蛋白酪氨酸磷酸酶 mu (PTP mu)，而更具侵袭性的星形细胞瘤、多形性胶质母细胞瘤 (GBM) 下调全长 PTP mu 表达。 GBM 中 PTP mu 表达的丧失是由于蛋白水解裂解产生 PTP mu 的细胞内片段和可能的裂解和释放的细胞外片段。在这里，我们鉴定出含有 PTP mu 介导的粘附所需结构域的切割细胞外片段仍然与 GBM 肿瘤组织相关。我们假设检测该片段将成为脑内肿瘤组织定位的绝佳诊断工具。为此，我们生成了一系列结合 PTP mu 片段的荧光标记肽探针。肽探针特异性识别手术切除的人类肿瘤组织切片中的 GBM 细胞。为了测试肽探针是否能够在体内检测GBM肿瘤，在小鼠胁腹和颅内异种移植人胶质母细胞瘤肿瘤模型系统中测试了PTP mu肽探针。使用 Maestro FLEX 体内成像系统，在尾静脉注射后几分钟内，用 PTP mu 肽探针对神经胶质瘤进行分子标记。标签可稳定至少 3 小时。总之，这些结果表明 PTP mu 胞外片段的肽识别为检测人类胶质母细胞瘤提供了一种新的分子诊断工具。这种工具具有明确的转化应用，可能会改善患有这种破坏性疾病的患者的手术切除和预后。
We recently found that normal human brain and low-grade astrocytomas express the receptor protein tyrosine phosphatase mu (PTP mu) and that the more invasive astrocytomas, glioblastoma multiforme (GBM), downregulate full-length PTP mu expression. Loss of PTP mu expression in GBMs is due to proteolytic cleavage that generates an intracellular and potentially a cleaved and released extracellular fragment of PTP mu. Here, we identify that a cleaved extracellular fragment containing the domains required for PTP mu-mediated adhesion remains associated with GBM tumor tissue. We hypothesized that detection of this fragment would make an excellent diagnostic tool for the localization of tumor tissue within the brain. To this end, we generated a series of fluorescently tagged peptide probes that bind the PTP mu fragment. The peptide probes specifically recognize GBM cells in tissue sections of surgically resected human tumors. To test whether the peptide probes are able to detect GBM tumors in vivo, the PTP mu peptide probes were tested in both mouse flank and intracranial xenograft human glioblastoma tumor model systems. The glial tumors were molecularly labeled with the PTP mu peptide probes within minutes of tail vein injection using the Maestro FLEX In Vivo Imaging System. The label was stable for at least 3 hours. Together, these results indicate that peptide recognition of the PTP mu extracellular fragment provides a novel molecular diagnostic tool for detection of human glioblastomas. Such a tool has clear translational applications and may lead to improved surgical resections and prognosis for patients with this devastating disease.