title: The impact of EBV and HIV infection on the microenvironmental niche underlying Hodgkin lymphoma pathogenesis.
abstract: The pathogenesis of classical Hodgkin lymphoma (cHL) is still enigmatic, largely because its tumor cells, the so-called Hodgkin and Reed-Stenberg (HRS) cells, invariably reside in a prominent reactive microenvironment, are rare and therefore difficult to analyze. On the other hand, the broadly investigated cHL-derived cell lines are not unequivocally considered as suitable and representative models for this puzzling disease. Based on current knowledge, it appears that the cross talk between the tumor cells and the reactive infiltrate of the microenvironment is complex and that multiple mechanisms occur, making cHL a very heterogeneous disease. In 20-40% of cHL cases, HRS cells carry a monoclonal infection by Epstein Barr virus (EBV), which is considered a tumor-initiating factor. In these cases, EBV shows a latency type II infection pattern with the expression of latent membrane protein-1 (LMP-1), a viral oncoprotein that mimics CD40 activation. This scenario is particularly intriguing for the pathogenesis of cHL arising in HIV-infected patients, which, for still obscure reasons, is invariably EBV-associated with LMP-1 expression in HRS cells. Recent evidences are consistent with the occurrence of different pathogenic pathways variably triggered by virus infections (EBV and HIV), genetic alterations, and interactions with critical microenvironmental components. This review focuses on the different microenvironmental niches that characterize cHL of the general population as well as cases of HIV-infected patients. A more comprehensive understanding of the complex interplay existing between HRS and tumor microenvironment is pivotal for the development of more effective treatments, particularly for relapsed or refractory diseases.
authors.affiliation: Department of Pathology, Centro di Riferimento Oncologico - IRCCS, National Cancer Institute, Aviano, PN, Italy.
authors.forename: Antonino
authors.initials: A
authors.lastname: Carbone
authors.affiliation: Department of Diagnostic Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy.
authors.forename: Annunziata
authors.initials: A
authors.lastname: Gloghini
authors.affiliation: Department of Molecular and Translational Medicine, University of Brescia Medical School, Brescia, Italy.
authors.forename: Arnaldo
authors.initials: A
authors.lastname: Caruso
authors.affiliation: Molecular Virology Unit and Scientific Directorate, Centro di Riferimento Oncologico - IRCCS, National Cancer Institute, Aviano, PN, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: De Paoli
authors.affiliation: Cancer Bio-Immunotherapy Unit, Centro di Riferimento Oncologico - IRCCS, National Cancer Institute, Aviano, PN, Italy.|University of Queensland Diamantina Institute, Translational Research Institute, University of Queensland, Brisbane, QLD, Australia.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Dolcetti
mesh_terms: D015703:Antigens, CD / Q000096:biosynthesis / Q000276:immunology; D016175:B-Lymphocyte Subsets / Q000276:immunology / Q000821:virology; D055028:Comparative Genomic Hybridization; D016207:Cytokines / Q000502:physiology; D000070819:Discoidin Domain Receptor 1 / Q000502:physiology; D020031:Epstein-Barr Virus Infections / Q000276:immunology / Q000503:physiopathology* / Q000821:virology; D005347:Fibroblasts / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic; D006689:Hodgkin Disease / Q000145:classification / Q000209:etiology / Q000276:immunology / Q000473:pathology / Q000821:virology*; D006801:Humans; D007121:Immunocompetence; D008213:Lymphocyte Activation; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D016483:Lymphoma, AIDS-Related / Q000209:etiology / Q000276:immunology / Q000473:pathology / Q000821:virology*; D008264:Macrophages / Q000502:physiology; D008954:Models, Biological; D009363:Neoplasm Proteins / Q000502:physiology; D016539:Reed-Sternberg Cells / Q000821:virology; D015398:Signal Transduction; D059016:Tumor Microenvironment; D014763:Viral Matrix Proteins / Q000502:physiology*; D017735:Virus Latency
chemical_list: D015703:Antigens, CD; D016207:Cytokines; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D009363:Neoplasm Proteins; D014763:Viral Matrix Proteins; C092030:DDR1 protein, human; D000070819:Discoidin Domain Receptor 1
keywords: EBV-associated Hodgkin lymphoma; HIV-associated Hodgkin lymphoma; Hodgkin lymphoma; classical Hodgkin lymphoma; microenvironment; pathogenesis