卡波济肉瘤ppt课件

Disorders associated with G protein-coupled receptors-Kaposis sarcoma(卡波济肉瘤)1040800114卡波济肉瘤课件Disorders associated with G pr1n有关卡波济肉瘤基本常识n有关卡波济肉瘤的细胞学机理n卡波济肉瘤的治疗卡波济肉瘤课件有关卡波济肉瘤基本常识卡波济肉瘤课件2卡波济肉瘤n一种免疫缺陷的机会性肿瘤，一种皮肤的多发性血管性肉瘤，也称为“特发性多发性出血性肉瘤”n艾滋病病人独具的一种恶性肿瘤，它很少在非艾滋病病人身上发生。是艾滋病病人直接死亡的原因之一，也是我国艾滋病诊断标准的一项依据n奥地利皮肤病专家Kaposi（卡波济）1872年报道 卡波济肉瘤课件卡波济肉瘤一种免疫缺陷的机会性肿瘤，一种皮肤的多发性血管性肉3临床特征n多见于躯干、四肢，也可见于面部、颈部、胸部、腹部、皮肤的多发性红斑或紫色的斑块损害，为稍微隆起的硬结，压之无疼痛，不褪色；也可见于口腔黏膜及上消化道黏膜或淋巴结周围。n以后累及肝、脾、胃、肠管、肺、脑、胰腺、膀胱、睾丸、前列腺（男性）、子宫、卵巢（女性）。卡波济肉瘤课件临床特征多见于躯干、四肢，也可见于面部、颈部、胸部、腹部、皮4n临床上至少可分为四型 经典型或欧洲型 非洲型 爱滋病型 移植物有关的卡波济肉瘤 卡波济肉瘤课件临床上至少可分为四型卡波济肉瘤课件5经典型或欧洲型n较稀少,见于东欧,意大利和俄罗斯 n病因病因：未明。可能与一种不明原因的感染因子有关系卡波济肉瘤课件经典型或欧洲型较稀少,见于东欧,意大利和俄罗斯 卡波济肉瘤课6非洲型（地方性非洲型（地方性Kaposi肉瘤）肉瘤）n主要侵犯年轻人，男女比例为13-17：1，以类似于经典Kaposi肉瘤的表面良性结节为特征。常常在5-8年内死亡，小孩可发生淋巴结病型。卡波济肉瘤课件非洲型（地方性Kaposi肉瘤）主要侵犯年轻人，男女比例为17爱滋病型(AIDS相关Kaposi肉瘤)流行病学流行病学：大多数此类病人是男同性恋，男女比例为106：1(why？)，HIV阳性患者发展成Kaposi肉瘤的总危险率是正常人的20，000倍。平均生存时间为17月。症状与体征症状与体征：多中心、对称性疾病。斑疹、斑片、丘疹或结节可发生在皮肤或黏膜的任何位置，尤其是口腔、鼻、耳后、躯干、阴茎、腿与足。淋巴结病很常见，常有疼痛性溃疡、肢体湿疹。内脏常见有胃肠道与肺的受累，任何脏器均可受累。卡波济肉瘤课件爱滋病型(AIDS相关Kaposi肉瘤)卡波济肉瘤课件8移植物有关的卡波济肉瘤(免役抑制型)n 常发生在免役抑制的器官移植患者，年龄约20-60岁，病程可慢可快，由于免疫抑制药物的不连续应用经常发生复发。卡波济肉瘤课件移植物有关的卡波济肉瘤(免役抑制型)常发生在免役抑制的器官9Kaposis sarcoma-associated herpesvirus（人疱疹病毒8型）nIn 1994,the Kaposis sarcoma-associated herpesvirus(KSHV/HHV-8)was identified as the etiologic agent（致病的相关因子）of Kaposis sarcoma(KS).which gene contributes to the initiation of KS？卡波济肉瘤课件Kaposis sarcoma-associated he10latent genes：blue lytic genes ：red卡波济肉瘤课件latent genes：blue 卡波济肉瘤课件11nLatent genes are expressed in almost all spindle cells in late KS lesions nLytic genes are expressed during the phase of the viral life cycle when viral progeny are produced.these viral genes are expressed in cells ultimately destined to die(lyse)卡波济肉瘤课件Latent genes are expressed in 12KSHV vGPCR responsible for the initiation of KS nevidence 1.when a KS model in which endothelial-specific retroviral transduction was used,vGPCR produced vascular tumors in mice 2.two transgenic animals that express vGPCR under either a ubiquitous(SV40)promoter or a T cell-specific promoter only manifest vascular tumors 卡波济肉瘤课件KSHV vGPCR responsible for th13nHHV-8的ORE74可编码一种G蛋白相连的受体，它以一种组成型（非拮抗剂依赖）方式，刺激与细胞增殖相联的信号传导途径，导致细胞转化和肿瘤发生，并通过血管内皮生长因子、血管生成因子、锥体细胞生长因子介导，诱导血管生成。n这种受体是一种可利用细胞传导途径，诱导细胞转化的病毒癌基因及介导KSHV致瘤中心血管生成的激活剂。卡波济肉瘤课件HHV-8的ORE74可编码一种G蛋白相连的受体，它以一种组14信号传导途径hHV-8的ORF74G蛋白相连的受体 细胞增殖相联的信号传导途径 细胞转化和肿瘤发生刺激编码Aborted lytic cycle progression HIV-1 Tat.inflammation卡波济肉瘤课件信号传导途径hHV-8的ORF74G蛋白相连的受体 细15细胞内信号传导因子血管内皮生长因子血管生成因子卡波济肉瘤课件细胞内信号传导因子血管内皮生长因子血管生成因子卡波济肉瘤课件16nThe KSHV vGPCR is a member of the family of CXC chemokine G-protein-linked receptors.this receptor exhibits ligand-independent activities.nactivation of the serine-threonine kinase Akt by vGPCR may represent a critical intracellular pathway in the blockade of cell death卡波济肉瘤课件The KSHV vGPCR is a member of 17nvGPCR induces the secretion of angiogenic growth factors from expressing cells,including VEGF,IL-8,and Gro-suggesting that vGPCR may serve a role both in direct cell transformation and indirect(paracrine)cell transformation 卡波济肉瘤课件vGPCR induces the secretion of18Mechanisms control vGPCR 1)vGPCR is transcribed within the 3 end of a bicistronic mRNA,thus restricting its expression 2)Host cytokines(e.g.,SDF-1 ,IP-10)act as antagonists to vGPCR signaling卡波济肉瘤课件Mechanisms control vGPCR 1193)KSHV itself encodes a lytic gene,vMIP2,whose protein product acts as an antagonist to vGPCR signaling 4)As mentioned above,as a lytic gene,vGPCR is expressed in cells ultimately destined to die.卡波济肉瘤课件3)KSHV itself encodes a lytic20nProliferative signals initiated by vGPCR prolong lytic cell survival to ensure efficient viral replication.nproangiogenic growth factors secreted by vGPCR-expressing cells recruit neighboring endothelial cells that are then infected by the newly formed progeny virion.卡波济肉瘤课件Proliferative signals initiate21nHow can vGPCR be responsible for the initiation of KS tumors if its expression and signaling are so tightly controlled?卡波济肉瘤课件How can vGPCR be responsible f22nunder special circumstances(e.g.,HIV co-infection,inflammation,aborted lytic cycle progression),dysregulation of the normal viral program may result in nonlytic expression and enhanced signaling of vGPCR,ultimately manifesting as KS.卡波济肉瘤课件under special circumstances(e23n1)HIV Tat increases expression of KSHV lytic genes,including vGPCR,whose expression is significantly enhanced in aggressive AIDS-KS as compared with the more benign classical KS lesions n2)Several inflammatory cytokines released by HIV infected cells can increase vGPCR signaling卡波济肉瘤课件1)HIV Tat increases expressio24 The critical role for these locally released inflammatory cytokines for vGPCR oncogenesis was recently confirmed by a transgenic animal encoding a mutant vGPCR lacking a ligand binding domain that failed to manifest tumors despite its constitutive activity卡波济肉瘤课件 The critical role for thes25卡波济肉瘤课件卡波济肉瘤课件26KS治疗（1）联合治疗 长春花碱（Vinblastine）对AIDS的KS有明显疗效，开始剂量4mg，生理盐水或5%葡萄糖20-30ml静脉注射，在维持白细胞在2.5-3109/L的情况下，渐增至每次9mg，每周一次，6-8周。春新碱（Vincristine）与长春花硷相似，对AIDS的KS有一定疗效，1.4-2.0mg/次，用生理盐水20-30ml静脉注射，每周一次。卡波济肉瘤课件KS治疗卡波济肉瘤课件27 足叶乙甙（etoposide vepesid）是治疗AIDS的有效药物。博来霉素，阿霉素。（2）放射疗法，可缓解症状，有效剂量1800-3000rad。（3）局部液氮冷冻（4）免疫调节剂：干扰素、异丙肌苷、胸腺素、白细胞介素等（5）vGPCR 的抗体药物卡波济肉瘤课件 足叶乙甙（etoposide vepesid）是治疗AI28卡波济肉瘤课件thank you 卡波济肉瘤课件29