國家衛生研究院 NHRI:Item 3990099045/15736
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    Please use this identifier to cite or link to this item: http://ir.nhri.org.tw/handle/3990099045/15736


    Title: Haploinsufficiency of adenomatous polyposis coli coupled with kirsten rat sarcoma viral oncogene homologue activation and P53 loss provokes high-grade glioblastoma formation in mice
    Authors: Fang, KT;Su, CS;Layos, JJ;Lau, NYS;Cheng, KH
    Contributors: National Institute of Cancer Research
    Abstract: Simple Summary Glioblastoma multiforme (GBM) ranks as the most frequent form of primary malignant brain tumor. The prognosis for individuals diagnosed with this disease typically leads to a median survival of under two years. Here, we developed mouse models to better understand the genetic basis of GBM, a highly aggressive brain tumor. We found that certain genetic alterations, such as Kirsten rat sarcoma viral oncogene homologue (KRAS) activation and p53 deficiency, cooperate to initiate glioma tumorigenesis. Combining these alterations with adenomatous polyposis coli (APC) haploinsufficiency led to the rapid progression of GBM in the mice, resembling the human disease. These models are valuable for identifying early disease biomarkers and may offer insights for improving the diagnosis and treatment of this challenging brain tumor.Abstract Glioblastoma multiforme (GBM) is the most common and deadly type of brain tumor originating from glial cells. Despite decades of clinical trials and research, there has been limited success in improving survival rates. However, molecular pathology studies have provided a detailed understanding of the genetic alterations associated with the formation and progression of glioblastoma-such as Kirsten rat sarcoma viral oncogene homolog (KRAS) signaling activation (5%), P53 mutations (25%), and adenomatous polyposis coli (APC) alterations (2%)-laying the groundwork for further investigation into the biological and biochemical basis of this malignancy. These analyses have been crucial in revealing the sequential appearance of specific genetic lesions at distinct histopathological stages during the development of GBM. To further explore the pathogenesis and progression of glioblastoma, here, we developed the glial-fibrillary-acidic-protein (GFAP)-Cre-driven mouse model and demonstrated that activated KRAS and p53 deficiencies play distinct and cooperative roles in initiating glioma tumorigenesis. Additionally, the combination of APC haploinsufficiency with mutant Kras activation and p53 deletion resulted in the rapid progression of GBM, characterized by perivascular inflammation, large necrotic areas, and multinucleated giant cells. Consequently, our GBM models have proven to be invaluable resources for identifying early disease biomarkers in glioblastoma, as they closely mimic the human disease. The insights gained from these models may pave the way for potential advancements in the diagnosis and treatment of this challenging brain tumor.
    Date: 2024-03-04
    Relation: Cancers. 2024 Mar 04;16(5):Article number 1046.
    Link to: http://dx.doi.org/10.3390/cancers16051046
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=2072-6694&DestApp=IC2JCR
    Cited Times(Scopus): https://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=85187659973
    Appears in Collections:[Others] Periodical Articles

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