Development of the clinical diagnosis and treatment of CNS germinoma using KIT as a target

在中枢神经系统（CNS）生殖细胞肿瘤（GCT）的某些亚组中，例如卵黄囊肿瘤和绒毛膜癌，临床诊断可以通过检测特定的癌蛋白来确定，例如甲胎蛋白或HCG。虽然生殖细胞瘤是最常见的中枢神经系统巨细胞瘤，但尚无特异性的肿瘤标志物。在缺乏这种标记物的情况下，有效的治疗计划需要手术干预以获得组织学诊断。本研究的目的是建立生殖细胞瘤的特异性标志物，主要研究c-kit及其配体干细胞因子（SCF）。原癌基因c-kit是一种跨膜酪氨酸激酶受体，在生殖细胞的发育中起着至关重要的作用，并在多种肿瘤中异常表达。c-kit的一种可溶形式（s-kit），仅由胞外结构域组成，已被鉴定为 ...更多信息 功能分子。我们用免疫组织化学方法分析了c-kit和SCF的分布，以确定其在中枢神经系统GCT的各种组织学亚型中的表达谱。为探讨s-kit和SCF是否是一种新的临床标志物，采用双抗体夹心酶联免疫吸附试验（ELISA）检测了脑脊液（CSF）中s-kit和SCF的浓度。一些成熟的畸胎瘤成分c-kit和SCF呈弱免疫反应;合体滋养层巨细胞呈阴性。含生殖细胞瘤的肿瘤中s-kit的水平显著升高。CSF中s-kit浓度与临床病程相关，蛛网膜下腔播散者明显增高，同时，即使在s-kit浓度较低的CSF中，SCF水平也在生殖细胞瘤中增高。然而，SCF的特异性低于s-kit，因为SCF水平在其他类型的肿瘤如髓母细胞瘤中升高。因此，s-kit和SCF的组合似乎是有用的生殖细胞瘤的诊断在这一点上。少

In certain subgroupes of central nervous system(CNS) germ cell tumors(GCTs) such as yolk sac tumors and choriocarcinomas, clinical diagnosis could be determined by detecting specific oncoproteins, e.g. alpha-fetoprotein or HCG. So called "neoadjuvant therapy" can be immediatelyapplied without histological verification by craniotomy.Although germinomas are the most common CNS GCTs, no specific tumor marker(s) has been identified. In the absence of such a marker, effective treatment planning requires surgical intervention to obtain a histologic diagnosis. The aim of this study was to establish specific marker(s) for germinomas.In the present work, we focused on c-kit and its ligand, stem cell factor(SCF). The proto-oncogene c-kit is a transmembrane tyrosine kinase receptor that plays a crucial role in the development of germ cells and is aberrantly expressed in a variety of neoplasms. A soluble form of the c-kit(s-kit), composed of only the extracellular domain, has been identified as a … More functional molecule.We immunohistochemically analyzed the distribution of c-kit and SCF to determine its expression profile in various histologic subtypes of CNS GCTs. To examine whether s-kit or SCF represents a novel clinical marker, its concentration in cerebrospinal fluid(CSF) was assayed by sandwich enzyme-linked immunosorbent assay(ELISA).On the cell surface of germinomas, c-kit and SCF was diffusely positive. Some mature teratoma components were weakly immunoreactive for c-kit and SCF ; syncytiotrophoblastic giant cells were negative. The level of s-kit was significantly higher in germinoma-containing tumors. The CSF concentration of s-kit was correlated with the clinical course ; it was markedly higher in patients with subarachnoid dissemination.Meanwhile, the level of SCF also increased in germinoma even in CSF samples with low s-kit concentration. However, specificity of SCF was lower than s-kit, since level of SCF increased in other types of tumors such as medulloblastoma. Therefore, combination of s-kit and SCF seems to be useful for the diagnosis of germinoma at this point. Less