文章：

腺瘤性息肉病基因单倍体不足联合Kirsten大鼠肉瘤病毒癌基因同源物激活与P53缺失诱发小鼠高级别胶质母细胞瘤形成

Haploinsufficiency of Adenomatous Polyposis Coli Coupled with Kirsten Rat Sarcoma Viral Oncogene Homologue Activation and P53 Loss Provokes High-Grade Glioblastoma Formation in Mice

原文发布日期：4 March 2024

DOI: 10.3390/cancers16051046

类型: Article

开放获取: 是

英文摘要：

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.

摘要翻译： 

多形性胶质母细胞瘤（GBM）是最常见且致命的脑肿瘤类型，起源于胶质细胞。尽管经过数十年的临床试验与研究，其在提高生存率方面取得的进展有限。然而，分子病理学研究已详细揭示了与胶质母细胞瘤形成和进展相关的遗传改变——如Kirsten大鼠肉瘤病毒癌基因同源物（KRAS）信号激活（5%）、P53突变（25%）及腺瘤性结肠息肉病（APC）基因改变（2%）——为深入探索该恶性肿瘤的生物学与生化基础奠定了重要基础。这些分析对于揭示GBM发展过程中特定组织病理学阶段遗传病变的序贯出现至关重要。为进一步探究胶质母细胞瘤的发病机制与进展过程，本研究构建了胶质纤维酸性蛋白（GFAP）-Cre驱动的小鼠模型，证实了激活的KRAS与p53缺失在胶质瘤发生起始阶段分别发挥独特且协同的作用。此外，APC单倍体不足与Kras突变激活及p53缺失的组合导致GBM快速进展，其特征表现为血管周围炎症、大面积坏死区域及多核巨细胞形成。因此，我们的GBM模型因其高度模拟人类疾病的特点，已被证明是识别胶质母细胞瘤早期疾病生物标志物的宝贵资源。从这些模型中获得的认识，可能为这一难治性脑肿瘤的诊断与治疗领域的潜在进展开辟道路。

原文链接：

Haploinsufficiency of Adenomatous Polyposis Coli Coupled with Kirsten Rat Sarcoma Viral Oncogene Homologue Activation and P53 Loss Provokes High-Grade Glioblastoma Formation in Mice