title: Suppression of natural killer cells by sorafenib contributes to prometastatic effects in hepatocellular carcinoma.
abstract: Sorafenib, a multi-tyrosine kinase inhibitor, is a standard treatment for advanced hepatocellular carcinoma (HCC). The present study was undertaken to determine whether the growth and metastasis of HCC were influenced in mice receiving sorafenib prior to implantation with tumors, and to investigate the in-vivo and in-vitro effect of sorafenib on natural killer (NK) cells. In sorafenib-pretreated BALB/c nu/nu mice and C57BL/6 mice, tumor growth was accelerated, mouse survival was decreased, and lung metastasis was increased. However, the depletion of NK1.1(+) cells in C57BL/6 mice eliminated sorafenib-mediated pro-metastatic effects. Sorafenib significantly reduced the number of NK cells and inhibited reactivity of NK cells against tumor cells, in both tumor-bearing and tumor-free C57BL/6 mice. Sorafenib down-regulated the stimulatory receptor CD69 in NK cells of tumor-bearing mice, but not in tumor-free mice, and inhibited proliferation of NK92-MI cells, which is associated with the blocking of the PI3K/AKT pathway, and inhibited cytotoxicity of NK cells in response to tumor targets, which was due to impaired ERK phosphorylation. These results suggest immunotherapeutic approaches activating NK cells may enhance the therapeutic efficacy of sorafenib in HCC patients.
authors: Liver Cancer Institute and Zhongshan Hospital, Fudan University, Key Laboratory for Carcinogenesis and Cancer Invasion, The Chinese Ministry of Education, Shanghai, PR China.
authors: Qiang-Bo
authors: QB
authors: Zhang
authors: Hui-Chuan
authors: HC
authors: Sun
authors: Ke-Zhi
authors: KZ
authors: Zhang
authors: Qing-An
authors: QA
authors: Jia
authors: Yang
authors: Y
authors: Bu
authors: Miao
authors: M
authors: Wang
authors: Zong-Tao
authors: ZT
authors: Chai
authors: Quan-Bao
authors: QB
authors: Zhang
authors: Wen-Quan
authors: WQ
authors: Wang
authors: Ling-Qun
authors: LQ
authors: Kong
authors: Xiao-dong
authors: XD
authors: Zhu
authors: Lu
authors: L
authors: Lu
authors: Wei-Zhong
authors: WZ
authors: Wu
authors: Lu
authors: L
authors: Wang
authors: Zhao-You
authors: ZY
authors: Tang
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D000945:Antigens, Differentiation, T-Lymphocyte / Q000378:metabolism; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D006528:Carcinoma, Hepatocellular / Q000276:immunology* / Q000401:mortality / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D006801:Humans; D016867:Immunocompromised Host; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity; D020014:K562 Cells; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000276:immunology; D037181:Lectins, C-Type / Q000378:metabolism; D008113:Liver Neoplasms / Q000276:immunology* / Q000401:mortality / Q000473:pathology*; D008175:Lung Neoplasms / Q000473:pathology / Q000556:secondary; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D051379:Mice; D009362:Neoplasm Metastasis; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000077157:Sorafenib; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D000099192:CD69 Antigens
chemical_list: D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D000970:Antineoplastic Agents; D007166:Immunosuppressive Agents; D037181:Lectins, C-Type; D009536:Niacinamide; D010671:Phenylurea Compounds; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D019908:Proto-Oncogene Proteins c-raf; D000077157:Sorafenib; D000099192:CD69 Antigens