Loss of TRAIL-R does not affect thymic or intestinal tumor development in p53 and adenomatous polyposis coli mutant mice.
Loss of TRAIL-R does not affect thymic or intestinal tumor development in p53 and adenomatous polyposis coli mutant mice.
复制标题
TRAIL-R 的缺失不会影响 p53 和腺瘤性息肉病大肠杆菌突变小鼠的胸腺或肠道肿瘤的发展。
DOI：
10.1038/sj.cdd.4401523
复制
发表时间：
2005
影响因子：
12.4
通讯作者：
Winoto,A
中科院分区：
文献类型：
--
作者：
Yue,HH;Diehl,GE;Winoto,A
TRAIL（TNF相关凋亡诱导配体）和TRAIL受体最初是基于它们与肿瘤坏死因子（TNF）和TNF受体（TNFR）家族成员的同源性而分离的。1-3在人类中，已经表征了五种TRAIL受体。这些受体中的两种，DR 4和DR 5，含有称为死亡结构域的细胞内蛋白基序，其可以传递凋亡信号。另外两种受体DcR 1和DcR 2缺乏功能性死亡结构域，似乎作为诱饵受体来抑制TRAIL的信号传导。4第五种受体骨保护素（OPG）已被证明在体外结合TRAIL，但在生理温度下对配体的亲和力较低; 5因此，尚不清楚它是否是TRAIL的真正受体。在小鼠中，已经鉴定了一种全长信号受体（TRAIL-R）和两种缺乏死亡结构域的诱饵受体。6，7与Fas和TNFR一样，TRAIL-R以FADD和半胱天冬酶-8依赖性方式在广泛的转化细胞系中诱导凋亡。8-11与Fas和TNFR相反，大多数非转化细胞对TRAIL-R介导的死亡具有抗性; 1，12，13因此，人们对TRAIL作为癌症治疗剂的潜在作用非常感兴趣。几项研究已经检查了TRAIL/TRAIL-R信号传导在肿瘤免疫中的体内作用。在活化的CD 8 + T细胞、NK细胞和NKT细胞的表面上观察到TRAIL表达，这与它们通过TRAIL依赖性机制杀死肿瘤细胞的能力相关。14-16 TRAIL阻断抗体还可以抑制NK细胞对小鼠纤维肉瘤L929靶细胞的细胞毒性。17体内施用TRAIL导致小鼠中外源引入的TRAIL敏感性肿瘤消退。此外，TRAIL的阻断抗体可以增加甲基胆蒽（MCA）治疗的小鼠以及接种TRAIL敏感性肿瘤的小鼠中的肿瘤生长和转移。18，19最后，TRAIL缺陷型小鼠对MCA诱导的肿瘤发生更敏感，对植入的TRAIL敏感性肿瘤的排斥能力较低，并且对免疫抑制剂α-半乳糖神经酰胺（α-GalCer）的反应性较低。20，21这些数据表明，TRAIL可以在体内诱导肿瘤细胞的排斥或凋亡，但其在自发发展的肿瘤的免疫监视中的作用尚未得到充分研究。我们先前描述了TRAIL-R缺陷小鼠的产生，其不会自发地发展肿瘤（Diehl G，等人提交）。为了确定TRAIL/TRAIL-R通路在控制自发发展的肿瘤中所起的作用（如果有的话），我们将TRAIL-R无效等位基因杂交到p53缺陷型和Min（小鼠肠肿瘤）肿瘤模型中。22遗传了p53突变等位基因的个体易患多种肿瘤类型。缺乏p53的小鼠可以存活并正常发育，但50%的小鼠在20周龄时发生肿瘤，所有小鼠在6个月大时发生肿瘤。p53缺陷动物中的绝大多数肿瘤是淋巴瘤，使这些动物成为良好的淋巴瘤模型。大多数淋巴瘤是胸腺起源，主要由未成熟的CD 4/CD 8双阳性细胞组成。25 p53 β/β小鼠也发生肿瘤，尽管在更晚的年龄，并且这些肿瘤主要是肉瘤。在大多数情况下，这些动物的肿瘤发生伴随着野生型p53等位基因的丢失。22先前的研究表明TRAIL在控制p53肿瘤发生中的作用。19然而，在这些实验中，TRAIL中和...
TRAIL (TNF-Related Apoptosis-Inducing Ligand) and the TRAIL receptors were originally isolated based to their homology to tumor necrosis factor (TNF) and TNF receptor (TNFR) family members. 1–3 In humans, five TRAIL receptors have been characterized. Two of these receptors, DR4 and DR5, contain an intracellular protein motif known as a death domain, which can transmit an apoptotic signal. Two additional receptors, DcR1 and DcR2, lack a functional death domain and appear to function as decoy receptors to inhibit signaling by TRAIL. 4 The fifth receptor, osteoprotegerin (OPG), has been shown to bind TRAIL in vitro but has low affinity for the ligand at physiological temperatures; 5 therefore, it is unclear as to whether it is a true receptor for TRAIL. In mice, one full length signaling receptor (TRAIL-R) and two decoy receptors lacking death domains have been identified. 6, 7 Like Fas and TNFR, TRAIL-R induces apoptosis in a broad range of transformed cell lines in a FADD-and caspase-8-dependent manner. 8–11 In contrast to Fas and TNFR, most nontransformed cells are resistant to TRAIL-R-mediated death; 1, 12, 13 as a result, there is considerable interest in the potential role of TRAIL as a cancer therapeutic. Several studies have examined the in vivo role of TRAIL/TRAIL-R signaling in tumor immunity. TRAIL expression has been observed on the surface of activated CD8þ T cells, NK, and NKT cells, which correlated with their ability to kill tumor cells via a TRAIL-dependent mechanism. 14–16 TRAIL blocking antibodies can also inhibit NK cell cytotoxicity against mouse fibrosarcoma L929 target cells. 17 In vivo TRAIL administration led to regression of exogenously introduced TRAIL-sensitive tumors in mice. 13 In addition, blocking antibodies to TRAIL can increase tumor growth and metastasis in methylcholanthrene (MCA)-treated mice as well as mice inoculated with TRAIL-sensitive tumors. 18, 19 Finally, TRAIL-deficient mice are more sensitive to MCA-induced tumorigenesis, less able to reject implanted TRAIL-sensitive tumors, and less responsive to the immunotherapeutic agent alpha-galactosylceramide (a-GalCer). 20, 21 These data indicate that TRAIL can induce rejection or apoptosis of tumor cells in vivo, but its role in immune surveillance of spontaneously developing tumors has not been fully investigated. We previously described the generation of TRAIL-R-deficient mice, which do not spontaneously develop tumors (Diehl G, et al. submitted). To determine what role, if any, the TRAIL/TRAIL-R pathway plays in the control of spontaneously developing tumors, we crossed the TRAIL-R null allele into the p53-deficient and Min (for Mouse Intestinal Neoplasia) tumor models.The p53 tumor suppressor gene is mutated in a large percentage of human malignancies, including tumors of the colon, breast, lung, and brain. 22 Individuals who inherit a mutant allele of p53 are susceptible to a wide range of tumor types. Mice deficient for p53 are viable and develop normally, but 50% develop tumors by 20 weeks of age and all develop tumors by 6 months of age. 22–24 The vast majority of tumors in p53-deficient animals are lymphomas, making these animals a good lymphoma model. Most of the lymphomas are of thymic origin and are composed primarily of immature CD4/CD8 double-positive cells. 25 p53þ/À mice also develop tumors, although at a much later age, and these tumors are primarily sarcomas. In most cases, tumorigenesis in these animals is accompanied by loss of the wild-type p53 allele. 22 A previous study has suggested a role for TRAIL in the control of p53 tumorigenesis. 19 However, in these experiments, TRAIL neutralizing …