Extended survival of Pyk2 or FAK deficient orthotopic glioma xenografts
Extended survival of Pyk2 or FAK deficient orthotopic glioma xenografts
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DOI：
10.1007/s11060-008-9656-8
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发表时间：
2008-11-01
影响因子：
3.9
通讯作者：
Loftus, Joseph C.
中科院分区：
文献类型：
--
作者：
Lipinski, Christopher A.;Tran, Nhan L.;Loftus, Joseph C.
胶质母细胞瘤的疾病进展涉及肿瘤细胞与肿瘤周围微环境之间复杂的相互作用。恶性胶质瘤细胞在整个大脑中分散的倾向是该疾病的典型特征，预示着对手术切除、放疗和目前的化疗反应不佳。局灶黏附激酶FAK和Pyk2在胶质瘤中作为重要的信号效应器，通过刺激促迁移和增殖信号通路发挥作用。在目前的研究中，我们在颅内异种移植模型中检测了Pyk2和FAK在恶性胶质瘤病理生物学中的重要性。我们发现，与对照小鼠相比，通过RNA干扰特异性敲低Pyk2或FAK表达的胶质瘤细胞建立的异种移植物小鼠的存活率显著提高。此外，在异种移植物中，抑制Pyk2活性的效果与敲低Pyk2表达的效果进行了比较。在颅内异种移植瘤模型中，通过稳定表达自主FERM结构域抑制胶质瘤细胞中Pyk2活性可减缓疾病进展。相反，表达不抑制Pyk2活性的变体FERM结构域不会改变存活。这些结果证实了Pyk2和FAK在胶质瘤中的疾病相关性，并提出了一种针对Pyk2的治疗获益的新方法。
Disease progression of glioblastoma involves a complex interplay between tumor cells and the peri-tumor microenvironment. The propensity of malignant glioma cells to disperse throughout the brain typifies the disease and portends a poor response to surgical resection, radiotherapy, and current chemotherapeutics. The focal adhesion kinases FAK and Pyk2 function as important signaling effectors in glioma through stimulation of pro-migratory and proliferative signaling pathways. In the current study, we examined the importance of Pyk2 and FAK in the pathobiology of malignant glioma in an intracranial xenograft model. We show that mice with xenografts established with glioma cells with specific knockdown of Pyk2 or FAK expression by RNA interference had significantly increased survival compared to control mice. Furthermore, the effect of inhibition of Pyk2 activity in xenografts was compared to the effect of knockdown of Pyk2 expression. Inhibition of Pyk2 activity by stable expression an autonomous FERM domain in glioma cells slowed disease progression in the intracranial xenograft model. In contrast, expression of a variant FERM domain that does not inhibit Pyk2 activity did not alter survival. These results substantiate the disease relevance of both Pyk2 and FAK in glioma and suggest a novel approach to target Pyk2 for therapeutic benefit.