Bodey Bela, Bodey Vivian, Siegel Stuart E, Nasir Aejaz, Coppola Domenico, Hakam Ardeshir, Kaiser Hans E
Department of Pathology, University of Southern California, Keck School of Medicine, Los Angeles, CA, USA.
In Vivo. 2004 Sep-Oct;18(5):593-602.
During the physiological process of PCD, the cell initiates a sequence of events culminating in the disintegration of the cell into small, membrane-bound apoptotic bodies. The intrinsic part of the PCD program arises from the mitochondria when it releases cytochrome c from the mitochondrial intermembrane space into the cytosol, forming the caspase-activating complex or apoptosome. The family of caspases is involved in the execution of genetically controlled PCD. Caspase-3 is expressed in normal and neoplastically transformed human cells and, like other caspases, is synthesized as an inactive, 32kDa proenzyme. Caspase-6 cleaves nuclear mitotic apparatus protein (NuMA) and mediates the shrinkage and fragmentation of cell nuclei. Caspase-8 is an initiation caspase that activates the caspase cascade during apoptosis, while caspase-9 is the initiator caspase in the caspase cascade in apoptotic normal and neoplastically transformed cells. During our immunocytochemical study, a sensitive, four-step, alkaline phosphatase conjugated antigen detection technique was employed. The results did in fact demonstrate the presence of high apoptotic activity within the cellular microenvironment of high-grade astrocytomas and glioblastomas. The observations identified cytoplasmic expression of caspase-3 and caspase-6 in more than 50 per cent of tumor cells, caspase-8 and caspase-9 in more than 10 per cent of tumor cells in high-grade anaplastic ASTR and glioblastoma. The immunocytochemical expression pattern in about 10 per cent of the tumor cells for caspase-3 and caspase-6 and about 1 to 5 per cent of the tumor cells for caspase-8 and caspase-9 demonstrated a translocation tendency from the cytoplasm to the cell nuclei in the apoptotic cells. This phenomenon may play an important role in these tumors' maintenance of immune privilege and evasion of immune attacks. We suggest that caspase-3, -6, -8 and -9 immunocytochemistry could have prognostic and immunotherapeutic significance in the treatment of these highly malignant glial tumors.
在细胞程序性死亡（PCD）的生理过程中，细胞启动一系列事件，最终导致细胞解体为小的、有膜包裹的凋亡小体。PCD程序的内在部分源于线粒体，当它将细胞色素c从线粒体膜间隙释放到细胞质中时，形成半胱天冬酶激活复合物或凋亡小体。半胱天冬酶家族参与基因控制的PCD的执行。半胱天冬酶-3在正常和肿瘤转化的人类细胞中表达，与其他半胱天冬酶一样，它以无活性的32 kDa 酶原形式合成。半胱天冬酶-6切割核有丝分裂器蛋白（NuMA）并介导细胞核的收缩和碎片化。半胱天冬酶-8是一种起始半胱天冬酶，在细胞凋亡期间激活半胱天冬酶级联反应，而半胱天冬酶-9是凋亡正常和肿瘤转化细胞中半胱天冬酶级联反应的起始半胱天冬酶。在我们的免疫细胞化学研究中，采用了一种灵敏的、四步的、碱性磷酸酶偶联抗原检测技术。结果确实证明在高级别星形细胞瘤和胶质母细胞瘤的细胞微环境中存在高凋亡活性。观察发现，在高级别间变性星形细胞瘤和胶质母细胞瘤中，超过50%的肿瘤细胞中有半胱天冬酶-3和半胱天冬酶-6的细胞质表达，超过10%的肿瘤细胞中有半胱天冬酶-8和半胱天冬酶-9的表达。在约10%的肿瘤细胞中半胱天冬酶-3和半胱天冬酶-6以及在约1%至5%的肿瘤细胞中半胱天冬酶-8和半胱天冬酶-9的免疫细胞化学表达模式显示，在凋亡细胞中存在从细胞质向细胞核的转位趋势。这种现象可能在这些肿瘤维持免疫豁免和逃避免疫攻击中起重要作用。我们认为，半胱天冬酶-3、-6、-8和-9免疫细胞化学在这些高度恶性胶质肿瘤的治疗中可能具有预后和免疫治疗意义。
