TNFα antagonization alters NOS2 dependent nasopharyngeal carcinoma tumor growth.
Tumor necrosis factor (TNFα) is a pro-inflammatory cytokine which mediates via nitric oxide (NO) several carcinogenic processes. Increasing evidences suggest that NO promotes inflammation induced growth of nasopharyngeal carcinoma (NPC). In patients, TNFα synthesis associates with poor survival. To explore the effect of the cytokine on NO production and NOS2 dependent NPC growth, NO2(-) (nitrite) producing cells in patients were analyzed in vitro. We observed that patients' monocytes/macrophages (Mo/Ma) and primary tumor biopsies synthesized significant amounts of NO2(-). Interestingly, tumor explants derived NO2(-) levels were more important in elderly patients in comparison with juveniles. Endogenous TNFα neutralization with an anti-TNFα monoclonal antibody (mAb) successfully inhibited NO2(-) synthesis by blood mononuclear cells and tumor explants. Recombinant TNFα (rTNFα) enhanced NO2(-) synthesis and C666-1 NPC cell proliferation. NOS2 selective inhibition (1400W) and TNFα antagonization with an anti-TNFα mAb potently inhibited rTNFα induced C666-1 proliferation and NO2(-) production. Importantly, primary tumors treated with the anti-TNFα mAb also displayed reduced proliferation index (Ki67). Altogether, our results define monocytes/macrophages and the primary tumor as major sources of circulating NO2(-) in NPC patients and support the idea that antibody dependent inhibition of the TNFα/NOS2 pathway may alter NPC tumor growth.
Department of Cell and Molecular Biology, Team Cytokines and Nitric Oxide Synthases, Faculty of Biology, University Houari Boumediene USTHB, Bab-Ezzouar, Algiers, Algeria; Department of Biomedical Engineering, Boston University, Boston, MA, United States. Electronic address: mbourouba@usthb.dz.
Mehdi
M
Bourouba
Department of Cell and Molecular Biology, Team Cytokines and Nitric Oxide Synthases, Faculty of Biology, University Houari Boumediene USTHB, Bab-Ezzouar, Algiers, Algeria.
Ahmed-Amine
AA
Zergoun
Department of Biomedical Engineering, Boston University, Boston, MA, United States.
Joseph S
JS
Maffei
Central Laboratory for Anatomopathology, Mustapha Pacha Hospital, Algiers, Algeria.
Dalia
D
Chila
Oto-Rhyno-Laryngology Department, Mustapha Pacha Hospital, Algiers, Algeria.
Djamel
D
Djennaoui
Central Laboratory for Anatomopathology, Mustapha Pacha Hospital, Algiers, Algeria.
Fatima
F
Asselah
Central Laboratory for Anatomopathology, Mustapha Pacha Hospital, Algiers, Algeria.
Zine-Charef
ZC
Amir-Tidadini
Department of Cell and Molecular Biology, Team Cytokines and Nitric Oxide Synthases, Faculty of Biology, University Houari Boumediene USTHB, Bab-Ezzouar, Algiers, Algeria.
Chafia
C
Touil-Boukoffa
Department of Biomedical Engineering, Boston University, Boston, MA, United States.
Muhammad H
MH
Zaman
D000293:Adolescent; D000328:Adult; D000375:Aging; D000911:Antibodies, Monoclonal / Q000276:immunology; D002277:Carcinoma; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D019394:Ki-67 Antigen / Q000235:genetics; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D008875:Middle Aged; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000378:metabolism* / Q000473:pathology* / Q000648:ultrastructure; D009569:Nitric Oxide / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000276:immunology; D055815:Young Adult
D000911:Antibodies, Monoclonal; D019394:Ki-67 Antigen; C439524:TNF protein, human; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II
NPC; Nitric oxide; Proliferation; TNFα; Tumor