Stache Christina, Hölsken Annett, Schlaffer Sven-Martin, Hess Andreas, Metzler Markus, Frey Benjamin, Fahlbusch Rudolf, Flitsch Jörg, Buchfelder Michael, Buslei Rolf
Department of Neuropathology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
Brain Pathol. 2015 Jan;25(1):1-10. doi: 10.1111/bpa.12148. Epub 2014 May 19.
Adamantinomatous craniopharyngiomas (adaCP) cause hypothalamic pituitary dysfunction. Elucidation of pathomechanisms underlying tumor progression is essential for the development of targeted chemotherapeutic treatment options. In order to study the mechanisms of tumor outgrowth, we implanted human primary adaCP tissue from three different surgical specimens stereotactically into the brain of immunodeficient mice (n = 20). Three months after tumor inoculation, magnetic resonance imaging and histology confirmed tumor engraftment in all 20 mice (100%) that obtained tissue transplants. The lesions invaded adjoining brain tissue with micro finger-shaped protrusions. Immunohistochemical comparison of the primary tumor and xenotransplants revealed a similar amount of proliferation (Mib-1) and cytokeratin expression pattern (KL-1). Whole tumor reconstruction using serial sections confirmed whirl-like cell clusters with nuclear β-catenin accumulations at the tumor brain border. These whirls were surrounded by a belt of Claudin-1 expressing cells, showed an activated epidermal growth factor receptor (EGFR) and distinct CD133 as well as p21(WAF1/Cip1) positivity, indicating a tumor stem cell phenotype. Consistent with our previous in vitro studies, intracranial xenotransplants of adaCP confirmed cells with nuclear β-catenin and activated EGFR being the driving force of tumor outgrowth. This model provides the possibility to study in vivo tumor cell migration and to test novel treatment regimens targeting this tumor stem cell niche.
成釉细胞瘤型颅咽管瘤（adaCP）会导致下丘脑垂体功能障碍。阐明肿瘤进展的病理机制对于开发靶向化疗治疗方案至关重要。为了研究肿瘤生长的机制，我们将来自三个不同手术标本的人类原发性adaCP组织立体定向植入免疫缺陷小鼠（n = 20）的大脑中。肿瘤接种三个月后，磁共振成像和组织学证实所有20只接受组织移植的小鼠（100%）均发生了肿瘤植入。病变以微指状突起侵入相邻脑组织。原发性肿瘤和异种移植的免疫组织化学比较显示增殖量（Mib-1）和细胞角蛋白表达模式（KL-1）相似。使用连续切片进行的全肿瘤重建证实，在肿瘤与脑的边界处存在核β-连环蛋白积聚的漩涡状细胞簇。这些漩涡被一层表达Claudin-1的细胞所包围，显示出活化的表皮生长因子受体（EGFR）以及明显的CD133和p21（WAF1/Cip1）阳性，表明具有肿瘤干细胞表型。与我们之前的体外研究一致，adaCP的颅内异种移植证实，核β-连环蛋白和活化的EGFR阳性细胞是肿瘤生长的驱动力。该模型为研究体内肿瘤细胞迁移以及测试针对这种肿瘤干细胞微环境的新型治疗方案提供了可能性。
