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首页> 外文期刊>Anticancer Research: International Journal of Cancer Research and Treatment >Fas (APO-1, CD95) receptor expression and new options for immunotherapy in childhood medulloblastomas.
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Fas (APO-1, CD95) receptor expression and new options for immunotherapy in childhood medulloblastomas.

机译：Fas（APO-1，CD95）受体的表达和儿童髓母细胞瘤免疫治疗的新选择。

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摘要

Central nervous system (CNS) tumors are the most common solid neoplasms in children. Medulloblastomas (MEDs) resemble embryonic neuroectodermal stem cells and their immature, uncommitted neuronal and glial progeny. Apoptosis is a basic physiological process wherein the cell initiates a sequence of events culminating in the fragmentation of its DNA, nuclear collapse, and finally, disintegration of the cell into small, membrane-bound apoptotic bodies. Expression of Fas (APO-1, CD95) receptor (FasR) and programmed or active cell death (PCD) was studied in childhood MEDs with varying stages of malignancy, and cell differentiation features. The majority of neoplastically transformed, neuroectodermal in origin cells, particularly in MEDs, express FasR, whereas normal cells in the CNS do not. FasR is a transmembrane glycoprotein, which belongs to the nerve growth factor/tumor necrosis factor (NGF/TNF) receptor superfamily. Apoptosis within childhood PNETs/MEDs is triggered by the binding of FasR to its natural ligand (FasL) or by cross-linking with anti-section i FasR antibodies. The resence of FasL has also been detected in childhood glial tumors. Therefore, a spontaneous, cellular immunophenotype (IP) regulatory, intratumoral apoptotic cell death (autocrine suicide) is possible in childhood brain tumors during neoplastic growth and progression. During our systematic immunocytochemical screening, we employed formalin fixed, paraffin-wax embedded tissue sections, as well as frozen sections of 34 primary human childhood PNETs/MEDs. The use of a sensitive, indirect, six step immunoperoxidase or alkaline phosphatase conjugated streptavidin-biotin antigen detection technique, modified by us, provided excellent immunocyto-chemical results. A systematic observation of the presence of apoptosis related markers (especially FasR) and cells in PCD was carried out. A strong expression (intensity of staining: "A"-the highest possible; number of stained neoplastic cells: +3 to +4, between 50% to 90%) of FasR, was detected employing 4 microns thick, formalin fixed, paraffin-wax embedded tissue slides. The panel of normal tissues employed as positive and negative tissue controls demonstrated presence of FasR in the prenatal thymus, mature tonsils and colon epithelium. Certainly, the coexpression of FasR, FasL, and other PCD-related proteins have also been reported in other human malignancies: breast cancer, colorectal carcinomas, large granular lymphocytic leukemia of T or NK cell origin, melanomas, lung, prostate, pancreas, and hepatocellular carcinomas. The coexpression of both FasR and FasL on several neoplastic cell types may represent an effective mechanism for tumor escape of the cellular immunological response of the host. It has been well established that brain tumors and melanomas produce their autocrine FasL, and even become capable of switching their signal transduction from the PCD pathway to a tumor growth, proliferative pathway. It seems that the therapeutical use of FasR-FasL (main apoptotic pathway) represents a new and exciting immunotherapeutical possibility in the treatment of primary childhood neuroectodermal tumors.
机译：中枢神经系统（CNS）肿瘤是儿童中最常见的实体瘤。髓母细胞瘤（MEDs）类似于胚胎神经外胚层干细胞及其未成熟，未定型的神经元和神经胶质子代。凋亡是一种基本的生理过程，其中细胞引发一系列事件，这些事件最终导致其DNA断裂，核塌陷，最后使细胞分解成膜结合的小凋亡小体。 Fas（APO-1，CD95）受体（FasR）的表达和程序性或活动性细胞死亡（PCD）在儿童MED中进行了研究，其恶性程度不同，并且具有细胞分化特征。原始细胞中的大多数肿瘤转化的神经外胚层细胞，特别是在MED中，大多数表达FasR，而CNS中的正常细胞则不表达。 FasR是跨膜糖蛋白，属于神经生长因子/肿瘤坏死因子（NGF / TNF）受体超家族。 FasR与其天然配体（FasL）的结合或与抗I型FasR抗体的交联触发了儿童PNET / MEDs中的凋亡。 FasL的抵抗力也已在儿童神经胶质瘤中发现。因此，在肿瘤生长和进展期间的儿童脑肿瘤中，自发的细胞免疫表型（IP）调节性肿瘤内凋亡细胞死亡（自分泌自杀）是可能的。在我们系统的免疫细胞化学筛选过程中，我们采用了福尔马林固定的，石蜡蜡包埋的组织切片以及34种人类儿童PNET / MED的冷冻切片。经我们修改的灵敏，间接，六步免疫过氧化物酶或碱性磷酸酶偶联的链霉亲和素-生物素抗原检测技术的使用，提供了出色的免疫细胞化学结果。对PCD中凋亡相关标记（尤其是FasR）和细胞的存在进行了系统的观察。使用4微米厚，福尔马林固定，石蜡-检测到FasR的强表达（染色强度：“ A”-可能最高;染色的肿瘤细胞数量：+3至+4，介于50％至90％之间）。蜡包埋的组织玻片。用作阳性和阴性组织对照的一组正常组织证明在产前胸腺，成熟扁桃体和结肠上皮中存在FasR。当然，FasR，FasL和其他PCD相关蛋白的共表达在其他人类恶性肿瘤中也有报道：乳腺癌，结肠直肠癌，T或NK细胞起源的大颗粒性淋巴细胞白血病，黑色素瘤，肺，前列腺，胰腺和肝细胞癌。 FasR和FasL在几种肿瘤细胞类型上的共表达可能代表了肿瘤逃逸宿主细胞免疫应答的有效机制。众所周知，脑肿瘤和黑素瘤会产生自分泌FasL，甚至能够将其信号转导从PCD途径转换为肿瘤生长，增殖途径。 FasR-FasL（主要的凋亡途径）的治疗用途似乎代表了治疗儿童期原发性神经外胚层肿瘤的一种新的令人兴奋的免疫治疗方法。

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