title: Toll-Like Receptor 1/2 and 5 Ligands Enhance the Expression of Cyclin D1 and D3 and Induce Proliferation in Mantle Cell Lymphoma.
abstract: Mantle cell lymphoma (MCL) is an aggressive B-cell non-Hodgkin's lymphoma with a still undefined etiology. Several lines of evidence are consistent with the possible involvement of peculiar microenvironmental stimuli sustaining tumor cell growth and survival, as the activation of Toll-like receptors (TLR) 4 and 9. However, little is known about the contribution of other TLRs of pathogenic relevance in the development of MCL. This study reports evidence that MCL cell lines and primary MCL cells express different levels of TLR2 and TLR5, and that their triggering is able to further activate the Akt, MAPK, and NF-κB signaling cascades, known to be altered in MCL cells. This leads to the enhancement of cyclin D1 and D3 over-expression, occurring at post-translational level through a mechanism that likely involves the Akt/GSK-3α/β pathway. Interestingly, in primary B cells, TLR1/2 or TLR5 ligands increase protein level of cyclin D1, which is not usually expressed in normal B cells, and cyclin D3 when associated with CD40 ligand (CD40L), IL-4, and anti-human-IgM co-stimulus. Finally, the activation of TLR1/2 and TLR5 results in an increased proliferation of MCL cell lines and, in the presence of co-stimulation with CD40L, IL-4, and anti-human-IgM also of primary MCL cells and normal B lymphocytes. These effects befall together with an enhanced IL-6 production in primary cultures. Overall, our findings suggest that ligands for TLR1/2 or TLR5 may provide critical stimuli able to sustain the growth and the malignant phenotype of MCL cells. Further studies aimed at identifying the natural source of these TLR ligands and their possible pathogenic association with MCL are warranted in order to better understand MCL development, but also to define new therapeutic targets for counteracting the tumor promoting effects of lymphoma microenvironment.
authors.affiliation: Cancer Bio-Immunotherapy Unit, Department of Translational Research, Centro di Riferimento Oncologico, IRCCS-National Cancer Institute, Aviano (PN), Italy.
authors.forename: Katy
authors.initials: K
authors.lastname: Mastorci
authors.affiliation: Cancer Bio-Immunotherapy Unit, Department of Translational Research, Centro di Riferimento Oncologico, IRCCS-National Cancer Institute, Aviano (PN), Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Muraro
authors.affiliation: Cancer Bio-Immunotherapy Unit, Department of Translational Research, Centro di Riferimento Oncologico, IRCCS-National Cancer Institute, Aviano (PN), Italy.|Princess Margaret Cancer Centre, University Health Network and TECHNA Institute for the Advancement of Technology for Health, TMDT, Room 11-314, 101 College Street, Toronto, ON M5G 1L7, Canada.
authors.forename: Elisa
authors.initials: E
authors.lastname: Pasini
authors.affiliation: Cancer Bio-Immunotherapy Unit, Department of Translational Research, Centro di Riferimento Oncologico, IRCCS-National Cancer Institute, Aviano (PN), Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Furlan
authors.affiliation: Cancer Bio-Immunotherapy Unit, Department of Translational Research, Centro di Riferimento Oncologico, IRCCS-National Cancer Institute, Aviano (PN), Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Sigalotti
authors.affiliation: Spirochete Laboratory, Department of Life Sciences, University of Trieste, Trieste, Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Cinco
authors.affiliation: Cancer Bio-Immunotherapy Unit, Department of Translational Research, Centro di Riferimento Oncologico, IRCCS-National Cancer Institute, Aviano (PN), Italy.|University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Australia.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Dolcetti
authors.affiliation: Cancer Bio-Immunotherapy Unit, Department of Translational Research, Centro di Riferimento Oncologico, IRCCS-National Cancer Institute, Aviano (PN), Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Fratta
mesh_terms: D023201:CD40 Ligand / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology*; D019938:Cyclin D1 / Q000378:metabolism*; D056743:Cyclin D3 / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006801:Humans; D015847:Interleukin-4 / Q000378:metabolism; D008024:Ligands; D020522:Lymphoma, Mantle-Cell / Q000378:metabolism*; D008228:Lymphoma, Non-Hodgkin / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D051194:Toll-Like Receptor 1 / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D051198:Toll-Like Receptor 5 / Q000378:metabolism*
chemical_list: D056743:Cyclin D3; D008024:Ligands; D016328:NF-kappa B; C495345:TLR4 protein, human; C495346:TLR5 protein, human; D051194:Toll-Like Receptor 1; D051197:Toll-Like Receptor 4; D051198:Toll-Like Receptor 5; D019938:Cyclin D1; D023201:CD40 Ligand; D015847:Interleukin-4; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases; D038362:Glycogen Synthase Kinase 3; C448021:glycogen synthase kinase 3 alpha