title: Role of the microenvironment in mantle cell lymphoma: IL-6 is an important survival factor for the tumor cells.
abstract: Mantle cell lymphoma (MCL) is an aggressive B-cell non-Hodgkin lymphoma frequently involved in the lymph nodes, bone marrow, spleen, and gastrointestinal tract. We examined the role of IL-6 in MCL. Human MCL cells expressed the membrane gp130 and soluble gp80, and some of them also secreted IL-6. Neutralizing autocrine IL-6 and/or blocking IL-6 receptors in IL-6(+)/gp80(+) MCL cells inhibited cell growth, enhanced the rate of spontaneous apoptosis, and increased sensitivity to chemotherapy drugs. For IL-6(-) or gp80(low) MCL cells, paracrine or exogenous IL-6 or gp80 protected the cells from stress-induced death. Knockdown of gp80 in gp80(high) MCL cells rendered the cells more sensitive to chemotherapy drugs, even in the presence of exogenous IL-6. In contrast, overexpression of gp80 in gp80(low)/IL-6(+) MCL cells protected the cells from chemotherapy drug-induced apoptosis in vitro and compromised the therapeutic effect of chemotherapy in vivo. IL-6 activated the Jak2/STAT3 and PI3K/Akt pathways in MCL, and the inhibition of these pathways completely or partially abrogated IL-6-mediated protection of MCL cells. Hence, our study identifies IL-6 as a key cytokine for MCL growth and survival and suggests that targeting the IL-6 pathway may be a novel way to improve the efficacy of chemotherapy in MCL patients.
authors.affiliation: Department of Lymphoma/Myeloma, Division of Cancer Medicine, Center for Cancer Immunology Research, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Liang
authors.initials: L
authors.lastname: Zhang
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
authors.forename: Jianfei
authors.initials: J
authors.lastname: Qian
authors.forename: Haiyan
authors.initials: H
authors.lastname: Li
authors.forename: Jorge E
authors.initials: JE
authors.lastname: Romaguera
authors.forename: Larry W
authors.initials: LW
authors.lastname: Kwak
authors.forename: Michael
authors.initials: M
authors.lastname: Wang
authors.forename: Qing
authors.initials: Q
authors.lastname: Yi
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D015153:Blotting, Western; D002470:Cell Survival / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D055785:Gene Knockdown Techniques; D006801:Humans; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism*; D020522:Lymphoma, Mantle-Cell / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D016513:Mice, SCID; D059016:Tumor Microenvironment / Q000276:immunology*
chemical_list: D015850:Interleukin-6