title: Toll-like receptor stimulation in splenic marginal zone lymphoma can modulate cell signaling, activation and proliferation.
abstract: Recent studies on splenic marginal zone lymphoma identified distinct mutations in genes belonging to the B-cell receptor and Toll-like receptor signaling pathways, thus pointing to their potential implication in the biology of the disease. However, limited data is available regarding the exact role of TLRs. We aimed at characterizing the expression pattern of TLRs in splenic marginal zone lymphoma cells and their functional impact on the activation, proliferation and viability of malignant cells in vitro. Cells expressed significant levels of TLR1, TLR6, TLR7, TLR8, TLR9 and TLR10 mRNA; TLR2 and TLR4 showed a low, variable pattern of expression among patients whereas TLR3 and TLR5 mRNAs were undetectable; mRNA specific for TLR signaling molecules and adapters was also expressed. At the protein level, TLR1, TLR6, TLR7, TLR9 and TLR10 were detected. Stimulation of TLR1/2, TLR2/6 and TLR9 with their respective ligands triggered the activation of IRAK kinases, MAPK and NF-κB signaling pathways, and the induction of CD86 and CD25 activation molecules, although in a heterogeneous manner among different patient samples. TLR-induced activation and cell viability were also inhibited by a specific IRAK1/4 inhibitor, thus strongly supporting the specific role of TLR signaling in these processes. Furthermore, TLR2/6 and TLR9 stimulation also significantly increased cell proliferation. In conclusion, we demonstrate that splenic marginal zone lymphoma cells are equipped with functional TLR and signaling molecules and that the stimulation of TLR1/2, TLR2/6 and TLR9 may play a role in regulating disease pathobiology, likely promoting the expansion of the neoplastic clone.
authors: Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milano, Italy Università degli studi di Pavia, Italy.
authors: Eleonora
authors: E
authors: Fonte
authors: Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milano, Italy.
authors: Andreas
authors: A
authors: Agathangelidis
authors: UOC Patologia Molecolare, IRCCS AOU S. Martino-IST Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy.
authors: Daniele
authors: D
authors: Reverberi
authors: Institute of Applied Biosciences, Centre For Research and Technology Hellas, Thessaloniki, Greece.
authors: Stavroula
authors: S
authors: Ntoufa
authors: Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milano, Italy Department of Onco-Hematology, San Raffaele Hospital, Milano, Italy Università Vita-Salute San Raffaele, Milano, Italy.
authors: Lydia
authors: L
authors: Scarfò
authors: Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milano, Italy.
authors: Pamela
authors: P
authors: Ranghetti
authors: UOC Patologia Molecolare, IRCCS AOU S. Martino-IST Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy.
authors: Giovanna
authors: G
authors: Cutrona
authors: Ospedale Niguarda, Milano, Italy.
authors: Alessandra
authors: A
authors: Tedeschi
authors: Institute of Applied Biosciences, Centre For Research and Technology Hellas, Thessaloniki, Greece.
authors: Aliki
authors: A
authors: Xochelli
authors: Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milano, Italy Department of Onco-Hematology, San Raffaele Hospital, Milano, Italy Università Vita-Salute San Raffaele, Milano, Italy.
authors: Federico
authors: F
authors: Caligaris-Cappio
authors: Department of Onco-Hematology, San Raffaele Hospital, Milano, Italy.
authors: Maurilio
authors: M
authors: Ponzoni
authors: Hematology Department, Nikea General Hospital, Athens, Greece.
authors: Chrysoula
authors: C
authors: Belessi
authors: Department of Haematology, Royal Bournemouth Hospital, UK.
authors: Zadie
authors: Z
authors: Davis
authors: Hospital Universitario Marques de Valdecilla and Instituto de Formación e Investigación Marqués de Valdecilla, Santander, Spain.
authors: Miguel A
authors: MA
authors: Piris
authors: Department of Haematology, Royal Bournemouth Hospital, UK.
authors: David
authors: D
authors: Oscier
authors: Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milano, Italy Department of Onco-Hematology, San Raffaele Hospital, Milano, Italy Università Vita-Salute San Raffaele, Milano, Italy ghia.paolo@hsr.it.
authors: Paolo
authors: P
authors: Ghia
authors: Institute of Applied Biosciences, Centre For Research and Technology Hellas, Thessaloniki, Greece Hematology Department and HCT Unit, G. Papanicolaou Hospital, Thessaloniki, Greece.
authors: Kostas
authors: K
authors: Stamatopoulos
authors: Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milano, Italy.
authors: Marta
authors: M
authors: Muzio
mesh_terms: D049109:Cell Proliferation; D005260:Female; D006801:Humans; D018442:Lymphoma, B-Cell, Marginal Zone / Q000378:metabolism* / Q000473:pathology; D008297:Male; D009363:Neoplasm Proteins / Q000378:metabolism*; D015398:Signal Transduction; D013160:Splenic Neoplasms / Q000378:metabolism* / Q000473:pathology; D051193:Toll-Like Receptors / Q000819:agonists* / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D009363:Neoplasm Proteins; D051193:Toll-Like Receptors