Insights into the Infiltrative Behavior of Adamantinomatous Craniopharyngioma in a New Xenotransplant Mouse Model

Abstract

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.

Preclinical transgenic and patient‐derived xenograft models recapitulate the radiological features of human adamantinomatous craniopharyngioma

“…MRI of nude mice bearing cerebral patient‐derived ACP xenografts was performed between 124 and 130 days after tumor implantation, at which time successful tumor engraftment had previously been confirmed histologically 26, under isoflurane anesthesia, on a 7T horizontal bore microimaging system (Bruker, Ettlingen, Germany) equipped with a dedicated mouse brain coil and an animal monitoring system. T 2 ‐weighted images ( T R  = 2370 ms, T E  = 41 ms, slice thickness = 0.7 mm, FOV = 24 mm × 38 mm, 210 × 320 matrix, pixel size = 119 µm × 119 µm) and T 1 ‐weighted contrast‐enhanced images prior to and following intravenous administration of 0.1 mmol/kg gadobutrol (Gadovist, Bayer Vital, Leverkusen, Germany) ( T R  = 500 ms, T E  = 9 ms, slice thickness = 0.7 mm, FOV = 24 mm × 28 mm, 448 × 512 matrix, pixel size = 55 µm × 55 µm) were acquired.…”

“…Lesions propagated in this manner show comparable tissue architecture and express similar immunohistochemical markers to the patient tumors, including whorl‐like cell clusters with nuclear β‐catenin accumulation and activated EGFR 26.…”

Molecular pathology of adamantinomatous craniopharyngioma: review and opportunities for practice

“…To model the disease, fresh surgically obtained ACP tissue has been used in vitro to isolate primary cell cultures, and recently, a new orthotopic xenograft model has been described. 12,22,50 Two genetically engineered models, expressing a functionally equivalent form of oncogenic b-catenin to that identified in human ACP, have given valuable insights into the processes underling tumorigenesis. 3,4,15 It is likely that to translate any new findings into novel therapeutic opportunities, a multidisciplinary approach combining several or all of these existing methodologies and perhaps new assays (e.g., circulating cell-free DNA (cfDNA) and proteomics) will be required.…”

60 YEARS OF NEUROENDOCRINOLOGY: Biology of human craniopharyngioma: lessons from mouse models

“…Logically, the activities of the clusters must be required to support tumour viability; otherwise, one must call into question why the scarce non-dividing cells are not eliminated, even though normal pituitary cells are mostly killed by the dividing tumour cells. In fact, using a xenograft mouse model, the Buslei group has shown that clusters are critical players in controlling cell behaviour and the infiltration of other tumour cells (Stache et al 2014). The paracrine model for the involvement of tissuespecific adult stem cells in tumorigenesis suggests that the cell that sustains the oncogenic mutation (mutant CTNNB1) and the cell-of-origin of the tumours are different (Fig.…”

“…In addition, these and a recent xenograft model (Stache et al 2014) represent a platform for testing novel treatments in pre-clinical studies.…”