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Production of a SCID mouse model of medulloblastoma to explore the therapeutic value of targeting tumor driver genes

ABSTRACT: Tumor driver genes are genes where structural or sequence mutations confer a selective advantage for cancer cells. The individualized targeting of tumor driver genes has become a topic of interest for tumor treatment. The prognosis for medulloblastoma (MB), a common type of malignant intracranial tumor found in children, is poor. The tumor driver genes and the corresponding targeted drugs remain to be studied. The present study analyzed tumor driver genes from tumor tissue and peripheral blood from one patient with nodular desmoplastic MB with Sonic Hedgehog activation and screened targeted drugs for the tumor driver genes. Additionally, MB tissue was successfully implanted into the SCID mouse which were then used for subsequent drug screening. The present study explored novel treatments for MB from the perspective of tumor driver genes, and may provide new ideas for choosing individualized targeted therapies for patients with MB.

SUBMITTER: Han Y

PROVIDER: S-EPMC7739861 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Project description:Severe Combined Immune Deficient (SCID)/Urokinase-type Plasminogen Activator (uPA) mice undergo liver failure and are useful hosts for the propagation of transplanted human hepatocytes (HH) which must compete with recipient-derived hepatocytes for replacement of the diseased liver parenchyma. While partial replacement by HH has proven useful for studies with Hepatitis C virus, complete replacement of SCID/uPA mouse liver by HH has never been achieved and limits the broader application of these mice for other areas of biomedical research. The herpes simplex virus type-1 thymidine kinase (HSVtk)/ganciclovir (GCV) system is a powerful tool for cell-specific ablation in transgenic animals. The aim of this study was to selectively eliminate murine-derived parenchymal liver cells from humanized SCID/uPA mouse liver in order to achieve mice with completely humanized liver parenchyma. Thus, we reproduced the HSVtk (vTK)/GCV system of hepatic failure in SCID/uPA mice.In vitro experiments demonstrated efficient killing of vTK expressing hepatoma cells after GCV treatment. For in vivo experiments, expression of vTK was targeted to the livers of FVB/N and SCID/uPA mice. Hepatic sensitivity to GCV was first established in FVB/N mice since these mice do not undergo liver failure inherent to SCID/uPA mice. Hepatic vTK expression was found to be an integral component of GCV-induced pathologic and biochemical alterations and caused death due to liver dysfunction in vTK transgenic FVB/N and non-transplanted SCID/uPA mice. In SCID/uPA mice with humanized liver, vTK/GCV caused death despite extensive replacement of the mouse liver parenchyma with HH (ranging from 32-87%). Surprisingly, vTK/GCV-dependent apoptosis and mitochondrial aberrations were also localized to bystander vTK-negative HH.Extensive replacement of mouse liver parenchyma by HH does not provide a secure therapeutic advantage against vTK/GCV-induced cytotoxicity targeted to residual mouse hepatocytes. Functional support by engrafted HH may be secured by strategies aimed at limiting this bystander effect.

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Production of a SCID mouse model of medulloblastoma to explore the therapeutic value of targeting tumor driver genes

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