Yurchenko M, Sidorenko S P
Department of Cell Regulation, R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology of NAS of Ukraine, Vasylkivska str. 45, 03022 Kyiv, Ukraine.
Exp Oncol. 2010 Dec;32(4):214-23.
The hallmark of Hodgkin's lymphoma (HL) are mononucleated Hodgkin's cells and multinucleated Reed-Sternberg (HRS) cells, which usually account for only about 1% of cells in the tumor tissue. The majority of HRS cells in classical HL are derived from germinal centre B cells that have acquired disadvantageous Ig variable chain gene mutations and escaped from apoptosis. Due to reprogramming of gene expression, these lymphoma cells have lost the expression of most B-cell specific genes and acquired expression of multiple genes that are typical for other hematopoietic cells. HRS cells attract various cells of immune system into lymphoma tissue resulting in an inflammatory microenvironment. Moreover, HRS cells are dependent on microenvironment, especially on survival signals from other cells. Despite the loss of BCR - the master-regulator of B cell fate, HRS cells express a number of receptors that regulate tumor cell survival. The rescue of HRS cells from apoptosis is a key event in HL pathogenesis. These cells express at least six receptors that belong to TNF receptor family: CD30, CD40, CD95, TACI, BCMA and RANK, co-stimulatory receptors CD80 and CD86, and E-selectins ligand CD15. Due to the mutations in genes encoding proteins of CD95-mediated apoptotic signaling pathway, it is not functional in HRS cells. Ligands of TNF family receptors on cells in HL microenvironment contribute to the activation of canonical and non-canonical NF-κB signaling pathways and survival program of HRS cells. Moreover, in HRS cells a number of multiple mutations in negative NF-κB regulators, and also gains and amplifications of positive regulators, cooperate in deregulating these pathways. All TNF receptors may be linked to the activation of prosurvival gene expression programs via Akt and ERK pathways. HRS cells also express CD150 receptor with specific ITSM motifs in the cytoplasmic tail. Ligation of this receptor on HRS cells induced activation of Akt and ERK pathways, and moreover, it triggered activation of JNK signaling cascade.
The review presents the current views on the role of cell surface receptors in maintenance of HL microenvironment favorable for HRS cells survival.
霍奇金淋巴瘤（HL）的标志是单核霍奇金细胞和多核里德-施特恩伯格（HRS）细胞，它们在肿瘤组织中通常仅占细胞总数的约1%。经典HL中的大多数HRS细胞源自生发中心B细胞，这些B细胞获得了不利的免疫球蛋白可变链基因突变并逃脱了凋亡。由于基因表达重编程，这些淋巴瘤细胞失去了大多数B细胞特异性基因的表达，并获得了其他造血细胞典型的多个基因的表达。HRS细胞将免疫系统的各种细胞吸引到淋巴瘤组织中，形成炎症微环境。此外，HRS细胞依赖于微环境，特别是依赖于来自其他细胞的生存信号。尽管失去了B细胞命运的主要调节因子BCR，但HRS细胞表达多种调节肿瘤细胞生存的受体。HRS细胞从凋亡中获救是HL发病机制中的关键事件。这些细胞表达至少六种属于肿瘤坏死因子受体家族的受体：CD30、CD40、CD95、TACI、BCMA和RANK、共刺激受体CD80和CD86，以及E-选择素配体CD15。由于编码CD95介导的凋亡信号通路蛋白的基因突变，它在HRS细胞中不起作用。HL微环境中细胞上肿瘤坏死因子家族受体的配体有助于激活经典和非经典的核因子κB信号通路以及HRS细胞的生存程序。此外，在HRS细胞中，负性核因子κB调节因子的多个突变以及正性调节因子的获得和扩增共同导致这些信号通路失调。所有肿瘤坏死因子受体都可能通过Akt和ERK信号通路与促生存基因表达程序的激活相关联。HRS细胞还在细胞质尾部表达具有特定免疫受体酪氨酸抑制基序（ITSM）基序的CD150受体。该受体在HRS细胞上的结合诱导了Akt和ERK信号通路的激活，此外，它还触发了JNK信号级联反应的激活。
本综述介绍了目前关于细胞表面受体在维持有利于HRS细胞生存的HL微环境中的作用的观点。
