title: Tumor microenvironment in diffuse large B-cell lymphoma: Matrixmetalloproteinases activation is mediated by osteopontin overexpression.
abstract: Non-Hodgkin lymphomas (NHL) are a heterogeneous group of lymphoproliferative malignancies with variable patterns of behavior and responses to therapy. NHL development and invasion depend on multiple interactions between tumor cells and non-neoplastic cells. Such interactions are usually modulated by several cytokines. Accordingly, it was demonstrated that matrix-metalloproteinase (MMP)-2 and MMP-9 were activated in human lymphoid cell lines by interleukin-6 (IL-6). The activation of these enzymes is associated with tumor invasion and metastasis in human cancers. MMPs are also activated in several cancers by osteopontin (OPN), a secreted glycoprotein that regulates cell adhesion, migration, and survival. However, it is still unclear if MMPs play a role in NHL development and if their activation is determined by OPN and/or IL-6. In the present study, two groups of 78 NHL patients and 95 healthy donors were recruited for the analysis of OPN, MMP-2, MMP-9 and IL-6.Significant higher circulating levels of MMP-2, MMP-9, OPN and IL-6 were observed in NHL patients when compared to healthy donors. Similar data were obtained by analyzing the activity of both MMP-2 and MMP-9. The multivariate regression model indicates that, in both NHL cases and healthy donors, OPN is associated with the increase of MMP-2 and MMP-9 levels independently of IL-6. These data were first confirmed by “in silico” analyses and then by “in vitro” experiments conducted on peripheral blood mononuclear cells randomly selected from both NHL patients and healthy donors.Overall, our data suggest that the activation of MMPs in NHL development is mostly associated with OPN. However, IL-6 may play an important role in the lymphomagenesis through the activation of other molecular pathways. This article is part of a Special Issue entitled: Tumor Microenvironment Regulation of Cancer Cell Survival, Metastasis, Inflammation, and Immune Surveillance edited by Peter Ruvolo and Gregg L. Semenza.
authors.affiliation: Department of Biomedical and Biotechnological Sciences, Section of General & Clinical Pathology and Oncology, University of Catania, Catania, Italy.
authors.forename: Grazia
authors.initials: G
authors.lastname: Malaponte
authors.affiliation: Department of Biomedical and Biotechnological Sciences, Section of General & Clinical Pathology and Oncology, University of Catania, Catania, Italy.
authors.forename: Sameh
authors.initials: S
authors.lastname: Hafsi
authors.affiliation: Unit of Epidemiology and Biostatistics, CRO Aviano National Cancer Institute, IRCCS, Aviano, Italy.
authors.forename: Jerry
authors.initials: J
authors.lastname: Polesel
authors.affiliation: Functional Genomics and Bioinformatics, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Castellano
authors.affiliation: Experimental Oncology 2, CRO, National Cancer Institute, IRCCS, Aviano, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Spessotto
authors.affiliation: Department of Clinical and Experimental Medicine, Section of Dermatology, University of Messina, Messina, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Guarneri
authors.affiliation: Functional Genomics and Bioinformatics, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Silvana
authors.initials: S
authors.lastname: Canevari
authors.affiliation: Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy.
authors.forename: Santo S
authors.initials: SS
authors.lastname: Signorelli
authors.affiliation: Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC, USA. Electronic address: mccubreyj@ecu.edu.
authors.forename: James A
authors.initials: JA
authors.lastname: McCubrey
authors.affiliation: Department of Biomedical and Biotechnological Sciences, Section of General & Clinical Pathology and Oncology, University of Catania, Catania, Italy. Electronic address: mlibra@unict.it.
authors.forename: Massimo
authors.initials: M
authors.lastname: Libra
mesh_terms: D002478:Cells, Cultured; D004789:Enzyme Activation; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015850:Interleukin-6 / Q000097:blood* / Q000235:genetics / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D016403:Lymphoma, Large B-Cell, Diffuse / Q000097:blood* / Q000235:genetics / Q000378:metabolism; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000097:blood* / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000097:blood* / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D015999:Multivariate Analysis; D053495:Osteopontin / Q000097:blood* / Q000235:genetics / Q000378:metabolism; D012044:Regression Analysis; D059016:Tumor Microenvironment
chemical_list: D015850:Interleukin-6; D053495:Osteopontin; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9
keywords: B-cell lymphomas; Interleukin-6; Matrixmetalloproteinase; Osteopontin