Hodgkin's lymphoma: the role of cell surface receptors in regulation of tumor cell fate

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.