APC Haploinsufficiency Cooperates With Kras and p53 Loss to Accelerate High Grade Glioblastoma Formation in Mice

• Main Authors: Chuan-Siang Su, 蘇傳翔
• Other Authors: Kuang-hung Cheng
• Format: Others
• Language: en_US
• Published: 2015
• Online Access: http://ndltd.ncl.edu.tw/handle/ehe3cf

碩士 === 國立中山大學 === 生物醫學研究所 === 103 === Glioblastoma multiforme (GBM) is the most common and deadest of brain tumor arising from glial cells. In contrast to other major cancers, decades of clinical trials have failed to provide appreciable survival benefit. Indeed, this continual cycle of clinical trial followed by failure has led to the clear conclusion that there is insufficient knowledge of the mechanisms underlying this lethal disease. Fortunately, molecular pathology studies have elucidated a detailed profile of genetic lesions associated with glioblastoma formation and progression—activation KRAS signaling (5%), P53 (25%) and APC (2%)—providing a foundation for investigation of the biological and biochemical basis for this malignancy. Significantly these analyses have revealed the sequential appearance of specific genetic lesions at defined histopathological stages of glioblastoma multiforme development. Here, we used a GFAP-Cre transgenic stain to determine that activated KRAS and p53 deficiency play specific and cooperative roles in the pathogenesis and progression of glioblastoma, and APC haploinsufficiency coupled with mutant Kras activation and p53 deletion resulted in the rapid progression of glioblastoma multiforme, exhibiting perivascular inflammation, large necrotic areas and some multinucleated giant cells. Thus, our mouse models are extremely valuable resources for the identification of early disease biomarkers in glioblastoma since they mimic so well the human disease. In addition, we employed proteomics and mass spectrometry based-imaging (MADLI-TOF) technologies to identify and trace candidate biomarkers in our mouse models, which will potentially help us to improve the diagnosis and treatments for glioblastoma.