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Molecular Proteomic Characterization of a Pediatric Medulloblastoma Xenograft.

ABSTRACT: Medulloblastoma (MBL), an archetypal primitive neuroectodermal tumor of the cerebellum, is the most common pediatric central nervous system malignancy representing approximately 20% of all childhood brain tumors. Herein, we report on a new xenotransplantable tumor cell line, derived from a 6-year-old female patient with cerebellar medulloblastoma, and the completele proteome molecular characterization of subsequent tumors from MBL xenotrasplanted mice.Tumors were grown in nude mice as subcutaneous xenografts (MBLX) composed of small round cells with hyperchromatic nuclei and scant cytoplasm. Tumor specimen were extracted from animals upon their sacrifice and their molecular proteomic content was analyzed by 2-DE coupled to MALDI-TOF MS analysis.Altogether 350 single-gene products were identified through the current approach, reported as the MBLX database.This new xenotransplantable tumor model, offers the scientific community valuable insight on the validity of xenografts altogether, while providing the means for a novel experimental model towards the study of human MBL.

SUBMITTER: Tsangaris GT

PROVIDER: S-EPMC5572304 | biostudies-literature | 2017 Jul-Aug

REPOSITORIES: biostudies-literature

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Molecular Proteomic Characterization of a Pediatric Medulloblastoma Xenograft.

Tsangaris George T GT Dimas Konstantinos K Malamou Angeliki A Katsafadou Angeliki A Papathanasiou Chrissa C Stravopodis Dimitrios J DJ Vorgias Constantinos E CE Gazouli Maria M Anagnostopoulos Athanasios K AK

Cancer genomics & proteomics 20170701 4

<h4>Background/aim</h4>Medulloblastoma (MBL), an archetypal primitive neuroectodermal tumor of the cerebellum, is the most common pediatric central nervous system malignancy representing approximately 20% of all childhood brain tumors. Herein, we report on a new xenotransplantable tumor cell line, derived from a 6-year-old female patient with cerebellar medulloblastoma, and the completele proteome molecular characterization of subsequent tumors from MBL xenotrasplanted mice.<h4>Materials and met ...[more]

PMID: 28647700

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Project description:BACKGROUND:Resistance to radiation treatment remains a major clinical problem for patients with brain cancer. Medulloblastoma is the most common malignant brain tumor of childhood, and occurs in the cerebellum. Though radiation treatment has been critical in increasing survival rates in recent decades, the presence of resistant cells in a substantial number of medulloblastoma patients leads to relapse and death. METHODS:Using the established medulloblastoma cell lines UW228 and Daoy, we developed a novel model system to enrich for and study radiation tolerant cells early after radiation exposure. Using fluorescence-activated cell sorting, dead cells and cells that had initiated apoptosis were removed, allowing surviving cells to be investigated before extensive proliferation took place. RESULTS:Isolated surviving cells were tumorigenic in vivo and displayed elevated levels of ABCG2, an ABC transporter linked to stem cell behavior and drug resistance. Further investigation showed another family member, ABCA1, was also elevated in surviving cells in these lines, as well as in early passage cultures from pediatric medulloblastoma patients. We discovered that the multi-ABC transporter inhibitors verapamil and reserpine sensitized cells from particular patients to radiation, suggesting that ABC transporters have a functional role in cellular radiation protection. Additionally, verapamil had an intrinsic anti-proliferative effect, with transient exposure in vitro slowing subsequent in vivo tumor formation. When expression of key ABC transporter genes was assessed in medulloblastoma tissue from 34 patients, levels were frequently elevated compared with normal cerebellum. Analysis of microarray data from independent cohorts (n = 428 patients) showed expression of a number of ABC transporters to be strongly correlated with certain medulloblastoma subtypes, which in turn are associated with clinical outcome. CONCLUSIONS:ABC transporter inhibitors are already being trialed clinically, with the aim of decreasing chemotherapy resistance. Our findings suggest that the inhibition of ABC transporters could also increase the efficacy of radiation treatment for medulloblastoma patients. Additionally, the finding that certain family members are associated with particular molecular subtypes (most notably high ABCA8 and ABCB4 expression in Sonic Hedgehog pathway driven tumors), along with cell membrane location, suggests ABC transporters are worthy of consideration for the diagnostic classification of medulloblastoma.

Dataset Information

Molecular Proteomic Characterization of a Pediatric Medulloblastoma Xenograft.

Publications

Molecular Proteomic Characterization of a Pediatric Medulloblastoma Xenograft.

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