Targeting the IL-6/JAK/STAT3 signalling axis in cancer

The IL-6/JAK/STAT3 pathway is aberrantly hyperactivated in many types of cancer, and such hyperactivation is generally associated with a poor clinical prognosis. In the tumour microenvironment, IL-6/JAK/STAT3 signalling acts to drive the proliferation, survival, invasiveness, and metastasis of tumour cells, while strongly suppressing the antitumour immune response. Thus, treatments that target the IL-6/JAK/STAT3 pathway in patients with cancer are poised to provide therapeutic benefit by directly inhibiting tumour cell growth and by stimulating antitumour immunity. Agents targeting IL-6, the IL-6 receptor, or JAKs have already received FDA approval for the treatment of inflammatory conditions or myeloproliferative neoplasms and for the management of certain adverse effects of chimeric antigen receptor T cells, and are being further evaluated in patients with haematopoietic malignancies and in those with solid tumours. Novel inhibitors of the IL-6/JAK/STAT3 pathway, including STAT3-selective inhibitors, are currently in development. Herein, we review the role of IL-6/JAK/STAT3 signalling in the tumour microenvironment and the status of preclinical and clinical investigations of agents targeting this pathway. We also discuss the potential of combining IL-6/JAK/STAT3 inhibitors with currently approved therapeutic agents directed against immune-checkpoint inhibitors.

[1]  Z. Culig,et al.  Interleukin-6: A multifunctional targetable cytokine in human prostate cancer , 2012, Molecular and Cellular Endocrinology.

[2]  V. Poli,et al.  Loss of STAT3 in murine NK cells enhances NK cell-dependent tumor surveillance. , 2014, Blood.

[3]  Y. Shima,et al.  Improvement in Castleman's disease by humanized anti-interleukin-6 receptor antibody therapy. , 2000, Blood.

[4]  M. Kuroda,et al.  MicroRNA-18a modulates STAT3 activity through negative regulation of PIAS3 during gastric adenocarcinogenesis , 2013, British Journal of Cancer.

[5]  T. Naoe,et al.  Phase I study of OPB-51602, an oral inhibitor of signal transducer and activator of transcription 3, in patients with relapsed/refractory hematological malignancies , 2015, Cancer science.

[6]  Lin Wang,et al.  Targeting Stat3 Abrogates EGFR Inhibitor Resistance in Cancer , 2012, Clinical Cancer Research.

[7]  Y. Sekine,et al.  Regulation of STAT3-mediated signaling by LMW-DSP2 , 2006, Oncogene.

[8]  J. Kremer,et al.  Placebo-controlled trial of tofacitinib monotherapy in rheumatoid arthritis. , 2012, The New England journal of medicine.

[9]  Lin Wang,et al.  Systemic Administration of a Cyclic Signal Transducer and Activator of Transcription 3 (STAT3) Decoy Oligonucleotide Inhibits Tumor Growth without Inducing Toxicological Effects , 2014, Molecular medicine.

[10]  D. Morris,et al.  Anti-inflammatory activity and neutrophil reductions mediated by the JAK1/JAK3 inhibitor, CP-690,550, in rat adjuvant-induced arthritis , 2010, Journal of Inflammation.

[11]  Xi Chen,et al.  A microRNA 221- and 222-Mediated Feedback Loop, via PDLIM2, Maintains Constitutive Activation of NFκB and STAT3 in Colorectal Cancer Cells , 2014 .

[12]  W. Sandborn,et al.  Tofacitinib as Induction and Maintenance Therapy for Ulcerative Colitis. , 2017, The New England journal of medicine.

[13]  Kevin Struhl,et al.  STAT3 activation of miR-21 and miR-181b-1 via PTEN and CYLD are part of the epigenetic switch linking inflammation to cancer. , 2010, Molecular cell.

[14]  Hua Yu,et al.  Role of Stat3 in suppressing anti-tumor immunity. , 2008, Current opinion in immunology.

[15]  Stefan Wirtz,et al.  TGF-β Suppresses Tumor Progression in Colon Cancer by Inhibition of IL-6 trans-Signaling , 2004 .

[16]  M. Sata,et al.  Essential Roles of IL-6 Trans-Signaling in Colonic Epithelial Cells, Induced by the IL-6/Soluble–IL-6 Receptor Derived from Lamina Propria Macrophages, on the Development of Colitis-Associated Premalignant Cancer in a Murine Model , 2009, The Journal of Immunology.

[17]  G. Mills,et al.  Direct Upregulation of STAT3 by MicroRNA-551b-3p Deregulates Growth and Metastasis of Ovarian Cancer. , 2016, Cell reports.

[18]  Jason Gotlib,et al.  A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. , 2012, The New England journal of medicine.

[19]  S. Leach,et al.  Emerging Strategies for Cancer Immunoprevention , 2015, Oncogene.

[20]  B. Goh,et al.  Phase I and biomarker study of OPB-51602, a novel signal transducer and activator of transcription (STAT) 3 inhibitor, in patients with refractory solid malignancies. , 2015, Annals of oncology : official journal of the European Society for Medical Oncology.

[21]  Q. Shen,et al.  Fragment-based drug design and identification of HJC0123, a novel orally bioavailable STAT3 inhibitor for cancer therapy. , 2013, European journal of medicinal chemistry.

[22]  B. Ghadimi,et al.  STAT3: A Novel Molecular Mediator of Resistance to Chemoradiotherapy , 2014, Cancers.

[23]  M. Kortylewski,et al.  Leukemia cell-targeted STAT3 silencing and TLR9 triggering generate systemic antitumor immunity. , 2014, Blood.

[24]  S. Rose-John,et al.  Interleukin-6 and its receptors: a highly regulated and dynamic system. , 2014, Cytokine.

[25]  T. Halstensen,et al.  Increased interleukin-6 expression is associated with poor prognosis and acquired cisplatin resistance in head and neck squamous cell carcinoma , 2016, Oncology reports.

[26]  Q. Mo,et al.  Small-molecule inhibition of STAT3 in radioresistant head and neck squamous cell carcinoma , 2016, Oncotarget.

[27]  R. Zinkernagel,et al.  Impaired immune and acute-phase responses in interleukin-6-deficient mice , 1994, Nature.

[28]  M. Loh,et al.  A phase 1 dosing study of ruxolitinib in children with relapsed or refractory solid tumors, leukemias, or myeloproliferative neoplasms: A Children's Oncology Group phase 1 consortium study (ADVL1011) , 2015, Pediatric blood & cancer.

[29]  Simon A. Jones,et al.  The soluble interleukin 6 receptor: mechanisms of production and implications in disease , 2001, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[30]  J. Furuse,et al.  Characterization of Patients With Advanced Pancreatic Cancer and High Serum Interleukin-6 Levels , 2015, Pancreas.

[31]  Y. Bang,et al.  Phase I Study of OPB-31121, an Oral STAT3 Inhibitor, in Patients with Advanced Solid Tumors , 2015, Cancer research and treatment : official journal of Korean Cancer Association.

[32]  J. Grandis,et al.  The STAT3 pathway as a therapeutic target in head and neck cancer: Barriers and innovations. , 2016, Oral oncology.

[33]  B. Monia,et al.  Preclinical evaluation of the toxicological effects of a novel constrained ethyl modified antisense compound targeting signal transducer and activator of transcription 3 in mice and cynomolgus monkeys. , 2013, Nucleic acid therapeutics.

[34]  J. Darnell,et al.  The JAK-STAT pathway at twenty. , 2012, Immunity.

[35]  B. Klein,et al.  Cloning and expression of an alternatively spliced mRNA encoding a soluble form of the human interleukin‐6 signal transducer gp130 1 , 1997, FEBS Letters.

[36]  P. Sonneveld,et al.  A phase 2 multicentre study of siltuximab, an anti‐interleukin‐6 monoclonal antibody, in patients with relapsed or refractory multiple myeloma , 2013, British journal of haematology.

[37]  Tuan-jie Li,et al.  Activation of STAT3 in Human Gastric Cancer Cells via Interleukin (IL)-6-Type Cytokine Signaling Correlates with Clinical Implications , 2013, PloS one.

[38]  Christopher Chiu,et al.  Infiltrating neutrophils mediate the initial angiogenic switch in a mouse model of multistage carcinogenesis , 2006, Proceedings of the National Academy of Sciences.

[39]  C. Madeddu,et al.  The role of interleukin-6 in the evolution of ovarian cancer: clinical and prognostic implications—a review , 2013, Journal of Molecular Medicine.

[40]  J. Scheller,et al.  Minimal Interleukin 6 (IL-6) Receptor Stalk Composition for IL-6 Receptor Shedding and IL-6 Classic Signaling , 2013, The Journal of Biological Chemistry.

[41]  S. Bortoluzzi,et al.  Activating somatic mutations outside the SH2-domain of STAT3 in LGL leukemia , 2015, Leukemia.

[42]  S. H. van der Burg,et al.  A phase I trial combining carboplatin/doxorubicin with tocilizumab, an anti-IL-6R monoclonal antibody, and interferon-α2b in patients with recurrent epithelial ovarian cancer. , 2015, Annals of oncology : official journal of the European Society for Medical Oncology.

[43]  E. Hurt,et al.  IL-6 Inhibition With MEDI5117 Decreases The Fraction of Head and Neck Cancer Stem Cells and Prevents Tumor Recurrence1,2 , 2016, Neoplasia.

[44]  Y. Iwamoto,et al.  Phosphorylation of signal transducer and activator of transcription 3 in soft tissue leiomyosarcoma is associated with a better prognosis , 2013, International journal of cancer.

[45]  W. Jian,et al.  Stat3 activation in urothelial stem cells leads to direct progression to invasive bladder cancer. , 2012, Cancer research.

[46]  D. C. Henckel,et al.  Case report. , 1995, Journal.

[47]  J. Rossi,et al.  A phase I/II study of siltuximab (CNTO 328), an anti-interleukin-6 monoclonal antibody, in metastatic renal cell cancer , 2010, British Journal of Cancer.

[48]  Michael C. Ostrowski,et al.  IL-6 and PD-L1 antibody blockade combination therapy reduces tumour progression in murine models of pancreatic cancer , 2016, Gut.

[49]  D. Nam,et al.  Phosphorylation of EZH2 activates STAT3 signaling via STAT3 methylation and promotes tumorigenicity of glioblastoma stem-like cells. , 2013, Cancer cell.

[50]  R. Bast,et al.  A phosphopeptide mimetic prodrug targeting the SH2 domain of Stat3 inhibits tumor growth and angiogenesis. , 2012, Journal of experimental therapeutics & oncology.

[51]  R. Kiesslich,et al.  TGF-beta suppresses tumor progression in colon cancer by inhibition of IL-6 trans-signaling. , 2004, Immunity.

[52]  Yunbao Pan,et al.  Stat3 Inhibitor Stattic Exhibits Potent Antitumor Activity and Induces Chemo- and Radio-Sensitivity in Nasopharyngeal Carcinoma , 2013, PloS one.

[53]  Ming Li,et al.  The IL-6/JAK/Stat3 feed-forward loop drives tumorigenesis and metastasis. , 2013, Neoplasia.

[54]  E. Casanova,et al.  Stat3 is a negative regulator of intestinal tumor progression in Apc(Min) mice. , 2010, Gastroenterology.

[55]  J. Bromberg.  Stat proteins and oncogenesis. , 2002, The Journal of clinical investigation.

[56]  S. Chimenti,et al.  Tofacitinib versus etanercept or placebo in moderate-to-severe chronic plaque psoriasis: a phase 3 randomised non-inferiority trial , 2015, The Lancet.

[57]  J. Bromberg,et al.  Targeting the tumor microenvironment , 2013, JAK-STAT.

[58]  J. Nemunaitis,et al.  Randomized, Double-Blind, Phase II Study of Ruxolitinib or Placebo in Combination With Capecitabine in Patients With Metastatic Pancreatic Cancer for Whom Therapy With Gemcitabine Has Failed. , 2015, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[59]  Renxiao Wang,et al.  A low-molecular-weight compound discovered through virtual database screening inhibits Stat3 function in breast cancer cells. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[60]  Suzanne F. Jones,et al.  Phase 1, open-label, dose-escalation, and pharmacokinetic study of STAT3 inhibitor OPB-31121 in subjects with advanced solid tumors , 2014, Cancer Chemotherapy and Pharmacology.

[61]  N. Okiyama,et al.  Varied immuno-related adverse events induced by immune-check point inhibitors - Nivolumab-associated psoriasiform dermatitis related with increased serum level of interleukin-6. , 2017, Nihon Rinsho Men'eki Gakkai kaishi = Japanese journal of clinical immunology.

[62]  Jiayuh Lin,et al.  Signal transducer and activator of transcription 3 is involved in cell growth and survival of human rhabdomyosarcoma and osteosarcoma cells , 2007, BMC Cancer.

[63]  O. Altundag,et al.  Interleukin-6 and C-reactive protein in metastatic renal cell carcinoma. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[64]  J. Machiels,et al.  A Phase I/II, Multiple-Dose, Dose-Escalation Study of Siltuximab, an Anti-Interleukin-6 Monoclonal Antibody, in Patients with Advanced Solid Tumors , 2014, Clinical Cancer Research.

[65]  H. Deeg,et al.  Phase 1/2 study of pacritinib, a next generation JAK2/FLT3 inhibitor, in myelofibrosis or other myeloid malignancies , 2016, Journal of Hematology & Oncology.

[66]  Sandra A. Moore,et al.  Activating alleles of JAK3 in acute megakaryoblastic leukemia. , 2006, Cancer cell.

[67]  D. McMillan,et al.  Routine clinical markers of the magnitude of the systemic inflammatory response after elective operation: a systematic review. , 2015, Surgery.

[68]  Simion I. Chiosea,et al.  First-in-human trial of a STAT3 decoy oligonucleotide in head and neck tumors: implications for cancer therapy. , 2012, Cancer discovery.

[69]  F. Vesuna,et al.  Interleukin-6 induces an epithelial–mesenchymal transition phenotype in human breast cancer cells , 2009, Oncogene.

[70]  H. Knüpfer,et al.  Serum interleukin-6 levels in colorectal cancer patients—a summary of published results , 2010, International Journal of Colorectal Disease.

[71]  S. Imbeaud,et al.  Frequent in-frame somatic deletions activate gp130 in inflammatory hepatocellular tumours , 2009, Nature.

[72]  Mikinori Sato,et al.  Interleukin-6 released by colon cancer-associated fibroblasts is critical for tumour angiogenesis: anti-interleukin-6 receptor antibody suppressed angiogenesis and inhibited tumour–stroma interaction , 2013, British Journal of Cancer.

[73]  Shicheng Guo,et al.  Hdac7 promotes lung tumorigenesis by inhibiting Stat3 activation , 2017, Molecular Cancer.

[74]  Toshiyuki Nakayama,et al.  Activation of STAT3 is a marker of poor prognosis in human colorectal cancer. , 2006, Oncology reports.

[75]  K. Pantel,et al.  The anti‐interleukin‐6 antibody siltuximab down‐regulates genes implicated in tumorigenesis in prostate cancer patients from a phase I study , 2011, The Prostate.

[76]  M. Tremblay,et al.  Protein Tyrosine Phosphatases, TC-PTP, SHP1, and SHP2, Cooperate in Rapid Dephosphorylation of Stat3 in Keratinocytes Following UVB Irradiation , 2010, PloS one.

[77]  M. Bidziński,et al.  The assessment of the prognostic value of tumor markers and cytokines as SCCAg, CYFRA 21.1, IL-6, VEGF and sTNF receptors in patients with squamous cell cervical cancer, particularly with early stage of the disease , 2015, Tumor Biology.

[78]  Kelsey P. Pendleton,et al.  Frequent mutation of receptor protein tyrosine phosphatases provides a mechanism for STAT3 hyperactivation in head and neck cancer , 2014, Proceedings of the National Academy of Sciences.

[79]  Hua Yu,et al.  Tumour immunology: Crosstalk between cancer and immune cells: role of STAT3 in the tumour microenvironment , 2007, Nature Reviews Immunology.

[80]  R. Jove,et al.  Src family kinases promote AML cell survival through activation of signal transducers and activators of transcription (STAT). , 2008, Leukemia research.

[81]  Kebin Liu,et al.  JAK-STAT-mediated chronic inflammation impairs cytotoxic T lymphocyte activation to decrease anti-PD-1 immunotherapy efficacy in pancreatic cancer , 2017, Oncoimmunology.

[82]  R. Figlin,et al.  STAT3: a target to enhance antitumor immune response. , 2011, Current topics in microbiology and immunology.

[83]  Nicholas B. Levine,et al.  miR-124 inhibits STAT3 signaling to enhance T cell-mediated immune clearance of glioma. , 2013, Cancer research.

[84]  K. Kiguchi,et al.  Disruption of Stat3 reveals a critical role in both the initiation and the promotion stages of epithelial carcinogenesis. , 2004, The Journal of clinical investigation.

[85]  H. Ueno,et al.  Phase 1 and pharmacological trial of OPB‐31121, a signal transducer and activator of transcription‐3 inhibitor, in patients with advanced hepatocellular carcinoma , 2015, Hepatology research : the official journal of the Japan Society of Hepatology.

[86]  J. Turkson,et al.  Phosphotyrosyl Peptides Block Stat3-mediated DNA Binding Activity, Gene Regulation, and Cell Transformation* , 2001, The Journal of Biological Chemistry.

[87]  A. Shiau,et al.  Constitutive activation of STAT3 and STAT5 is present in the majority of nasopharyngeal carcinoma and correlates with better prognosis , 2003, British Journal of Cancer.

[88]  M. Neurath,et al.  IL-6 Signaling Promotes Tumor Growth in Colorectal Cancer , 2005, Cell cycle.

[89]  R. Nomelini,et al.  Serum IL-6 and IL-8 Correlate with Prognostic Factors in Ovarian Cancer , 2017, Immunological investigations.

[90]  D. Frank,et al.  STAT signaling in the pathogenesis and treatment of myeloid malignancies , 2012, JAK-STAT.

[91]  S. Rose-John.  IL-6 Trans-Signaling via the Soluble IL-6 Receptor: Importance for the Pro-Inflammatory Activities of IL-6 , 2012, International journal of biological sciences.

[92]  S. Durum,et al.  The promise of Janus kinase inhibitors in the treatment of hematological malignancies , 2017, Cytokine.

[93]  Aijuan Qu,et al.  Signal Transducer and Activator of Transcription 4 in Liver Diseases , 2015, International journal of biological sciences.

[94]  N. Fusenig,et al.  IL‐6 promotes malignant growth of skin SCCs by regulating a network of autocrine and paracrine cytokines , 2011, International journal of cancer.

[95]  E. Hurt,et al.  A Novel IL6 Antibody Sensitizes Multiple Tumor Types to Chemotherapy Including Trastuzumab-Resistant Tumors. , 2016, Cancer research.

[96]  Hua Yu,et al.  Stat3 mediates myeloid cell-dependent tumor angiogenesis in mice. , 2008, The Journal of clinical investigation.

[97]  M. Griesshammer,et al.  Ruxolitinib versus standard therapy for the treatment of polycythemia vera. , 2015, The New England journal of medicine.

[98]  G. Fuller,et al.  Constitutive activation of Stat3α in brain tumors: localization to tumor endothelial cells and activation by the endothelial tyrosine kinase receptor (VEGFR-2) , 2002, Oncogene.

[99]  Francisco Cervantes,et al.  JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. , 2012, The New England journal of medicine.

[100]  M. Neurath,et al.  Soluble gp130 is the natural inhibitor of soluble interleukin-6 receptor transsignaling responses. , 2001, European journal of biochemistry.

[101]  Y. Saeki,et al.  Interleukin 6 plays a key role in the development of antigen-induced arthritis. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[102]  D. Oscier,et al.  Widespread occurrence of the JAK2 V617F mutation in chronic myeloproliferative disorders. , 2005, Blood.

[103]  Jiayuh Lin,et al.  LLL-3 inhibits STAT3 activity, suppresses glioblastoma cell growth and prolongs survival in a mouse glioblastoma model , 2009, British Journal of Cancer.

[104]  S. Mallet,et al.  Safety, tolerability and potential efficacy of injection of autologous adipose-derived stromal vascular fraction in the fingers of patients with systemic sclerosis: an open-label phase I trial , 2014, Annals of the rheumatic diseases.

[105]  T. Ashizawa,et al.  Antitumor activity of a novel small molecule STAT3 inhibitor against a human lymphoma cell line with high STAT3 activation. , 2011, International journal of oncology.

[106]  S. Akira,et al.  Stat3 and MMP7 contribute to pancreatic ductal adenocarcinoma initiation and progression. , 2011, Cancer cell.

[107]  D. Grandér,et al.  PD-L1 is commonly expressed and transcriptionally regulated by STAT3 and MYC in ALK-negative anaplastic large-cell lymphoma , 2017, Leukemia.

[108]  Hua Yu,et al.  STATs in cancer inflammation and immunity: a leading role for STAT3 , 2009, Nature Reviews Cancer.

[109]  J. Rossi,et al.  Siltuximab for multicentric Castleman's disease: a randomised, double-blind, placebo-controlled trial. , 2014, The Lancet. Oncology.

[110]  P. Yue,et al.  A novel small-molecule disrupts Stat3 SH2 domain-phosphotyrosine interactions and Stat3-dependent tumor processes. , 2010, Biochemical pharmacology.

[111]  R Berger,et al.  A TEL-JAK2 fusion protein with constitutive kinase activity in human leukemia. , 1997, Science.

[112]  H. Baumann,et al.  Targeting signal transducer and activator of transcription signaling pathway in leukemias. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[113]  W. Guida,et al.  Selective chemical probe inhibitor of Stat3, identified through structure-based virtual screening, induces antitumor activity , 2007, Proceedings of the National Academy of Sciences.

[114]  D. Lodygin,et al.  IL-6R/STAT3/miR-34a feedback loop promotes EMT-mediated colorectal cancer invasion and metastasis. , 2014, The Journal of clinical investigation.

[115]  A. Hobisch,et al.  Mcl-1 is regulated by IL-6 and mediates the survival activity of the cytokine in a model of late stage prostate carcinoma. , 2008, Advances in experimental medicine and biology.

[116]  H. Ludwig,et al.  Interleukin-6 is a prognostic factor in multiple myeloma [letter] [see comments] , 1991 .

[117]  R. Ralhan,et al.  Prognostic significance of nuclear pSTAT3 in oral cancer , 2011, Head & neck.

[118]  J. Grandis,et al.  Targeted inhibition of Stat3 with a decoy oligonucleotide abrogates head and neck cancer cell growth , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[119]  Lin Wang,et al.  Frequent promoter hypermethylation of PTPRT increases STAT3 activation and sensitivity to STAT3 inhibition in head and neck cancer , 2015, Oncogene.

[120]  B. Jenkins,et al.  Acquiring signalling specificity from the cytokine receptor gp130. , 2004, Trends in genetics : TIG.

[121]  R. Ahmed,et al.  STAT3, STAT4, NFATc1, and CTCF Regulate PD-1 through Multiple Novel Regulatory Regions in Murine T Cells , 2014, The Journal of Immunology.

[122]  J. Grandis,et al.  Requirement of Stat3 but not Stat1 activation for epidermal growth factor receptor- mediated cell growth In vitro. , 1998, The Journal of clinical investigation.

[123]  I. S. Omar,et al.  Cancer-associated fibroblasts promote endometrial cancer growth via activation of interleukin-6/STAT-3/c-Myc pathway. , 2016, American journal of cancer research.

[124]  C. Thiele,et al.  Inhibition of STAT3 with the Generation 2.5 Antisense Oligonucleotide, AZD9150, Decreases Neuroblastoma Tumorigenicity and Increases Chemosensitivity , 2016, Clinical Cancer Research.

[125]  Solomon H. Snyder,et al.  Erratum: Inositol polyphosphate multikinase is a coactivator of p53-mediated transcription and cell death (Science Signaling (2013) 6: 273 (er1) Doi: 10.1126/scisignal.6273er1) , 2013 .

[126]  P. Hojman,et al.  The role of intratumoral and systemic IL-6 in breast cancer , 2013, Breast Cancer Research and Treatment.

[127]  Kyongmin Kim,et al.  NF-κB and STAT3 cooperatively induce IL6 in starved cancer cells , 2012, Oncogene.

[128]  T. Naoe,et al.  A novel STAT inhibitor, OPB-31121, has a significant antitumor effect on leukemia with STAT-addictive oncokinases , 2013, Blood Cancer Journal.

[129]  A. Palumbo,et al.  Phase 2 randomized study of bortezomib-melphalan-prednisone with or without siltuximab (anti-IL-6) in multiple myeloma. , 2014, Blood.

[130]  A. Bhatt,et al.  Role of interleukin-6 in cancer progression and therapeutic resistance , 2016, Tumor Biology.

[131]  J. Scheller,et al.  The pro- and anti-inflammatory properties of the cytokine interleukin-6. , 2011, Biochimica et biophysica acta.

[132]  J. DiGiovanni,et al.  Constitutive activation and targeted disruption of signal transducer and activator of transcription 3 (Stat3) in mouse epidermis reveal its critical role in UVB-induced skin carcinogenesis , 2008, Oncogene.

[133]  Ho-June Lee,et al.  Drug resistance via feedback activation of Stat3 in oncogene-addicted cancer cells. , 2014, Cancer cell.

[134]  J. McCubrey,et al.  STAT transcription factors in hematopoiesis and leukemogenesis: opportunities for therapeutic intervention , 2014, Leukemia.

[135]  J. Grandis,et al.  In vivo antitumor efficacy of STAT3 blockade using a transcription factor decoy approach: implications for cancer therapy , 2005, Oncogene.

[136]  Hua Yu,et al.  Inhibiting Stat3 signaling in the hematopoietic system elicits multicomponent antitumor immunity , 2005, Nature Medicine.

[137]  J S Yudkin,et al.  The effect of novel polymorphisms in the interleukin-6 (IL-6) gene on IL-6 transcription and plasma IL-6 levels, and an association with systemic-onset juvenile chronic arthritis. , 1998, The Journal of clinical investigation.

[138]  M. Dimopoulos,et al.  A phase 2, randomized, double‐blind, placebo‐controlled study of siltuximab (anti‐IL‐6 mAb) and bortezomib versus bortezomib alone in patients with relapsed or refractory multiple myeloma , 2015, American journal of hematology.

[139]  J. Turkson,et al.  Novel peptidomimetic inhibitors of signal transducer and activator of transcription 3 dimerization and biological activity. , 2004, Molecular cancer therapeutics.

[140]  K. Kinzler,et al.  Identification of STAT3 as a substrate of receptor protein tyrosine phosphatase T , 2007, Proceedings of the National Academy of Sciences.

[141]  B. Preston,et al.  Case Series , 2010, Toxicologic pathology.

[142]  D. Wallach,et al.  Soluble cytokine receptors are present in normal human urine , 1989, The Journal of experimental medicine.

[143]  D. Sexton.  Tofacitinib versus methotrexate in rheumatoid arthritis. , 2014, The New England journal of medicine.

[144]  N. Reich,et al.  Dynamics of the STAT3 Transcription Factor: Nuclear Import Dependent on Ran and Importin-β1 , 2011, PloS one.

[145]  R. Figlin,et al.  Antiangiogenic and antimetastatic activity of JAK inhibitor AZD1480. , 2011, Cancer research.

[146]  F. Caimi,et al.  Emerging Opportunities and Challenges , 2005 .

[147]  W. Guida,et al.  A novel inhibitor of STAT3 homodimerization selectively suppresses STAT3 activity and malignant transformation. , 2013, Cancer research.

[148]  P. Yue,et al.  Orally bioavailable small-molecule inhibitor of transcription factor Stat3 regresses human breast and lung cancer xenografts , 2012, Proceedings of the National Academy of Sciences.

[149]  Y. Bang,et al.  OPB-31121, a novel small molecular inhibitor, disrupts the JAK2/STAT3 pathway and exhibits an antitumor activity in gastric cancer cells. , 2013, Cancer letters.

[150]  J. Grandis,et al.  Loss-of-Function PTPRD Mutations Lead to Increased STAT3 Activation and Sensitivity to STAT3 Inhibition in Head and Neck Cancer , 2015, PloS one.

[151]  Stephanie Kreis,et al.  Jaks and cytokine receptors--an intimate relationship. , 2006, Biochemical pharmacology.

[152]  S. Verstovsek,et al.  JAK2 inhibitors for myeloproliferative neoplasms: what is next? , 2017, Blood.

[153]  Mario Cazzola,et al.  A gain-of-function mutation of JAK2 in myeloproliferative disorders. , 2005, The New England journal of medicine.

[154]  D. Frank.  STAT3 as a central mediator of neoplastic cellular transformation. , 2007, Cancer letters.

[155]  K. Garcia,et al.  Signaling conformations of the tall cytokine receptor gp130 when in complex with IL-6 and IL-6 receptor , 2005, Nature Structural &Molecular Biology.

[156]  S. Jagannath,et al.  A Phase I, Open-Label Study of Siltuximab, an Anti–IL-6 Monoclonal Antibody, in Patients with B-cell Non-Hodgkin Lymphoma, Multiple Myeloma, or Castleman Disease , 2013, Clinical Cancer Research.

[157]  R. Bast,et al.  Potent and selective phosphopeptide mimetic prodrugs targeted to the Src homology 2 (SH2) domain of signal transducer and activator of transcription 3. , 2011, Journal of medicinal chemistry.

[158]  L. To,et al.  Results of a phase 2 study of pacritinib (SB1518), a JAK2/JAK2(V617F) inhibitor, in patients with myelofibrosis. , 2015, Blood.

[159]  Jia-Bin Huang,et al.  Icaritin Inhibits JAK/STAT3 Signaling and Growth of Renal Cell Carcinoma , 2013, PloS one.

[160]  Naveena Singh,et al.  Interleukin-6 as a Therapeutic Target in Human Ovarian Cancer , 2011, Clinical Cancer Research.

[161]  P. Dent,et al.  Rationally Repurposing Ruxolitinib (Jakafi®) as a Solid Tumor Therapeutic , 2016, Front. Oncol..

[162]  E. Li,et al.  The Opposing Function of STAT3 as an Oncoprotein and Tumor Suppressor Is Dictated by the Expression Status of STAT3β in Esophageal Squamous Cell Carcinoma , 2015, Clinical Cancer Research.

[163]  Can Alkan,et al.  Activating mutations of STAT5B and STAT3 in lymphomas derived from gamma delta-T or NK cells , 2022 .

[164]  Yan Liu,et al.  MicroRNA-218 functions as a tumor suppressor in lung cancer by targeting IL-6/STAT3 and negatively correlates with poor prognosis , 2017, Molecular Cancer.

[165]  S. Rose-John,et al.  Inhibition of IL‐6 signaling significantly reduces primary tumor growth and recurrencies in orthotopic xenograft models of pancreatic cancer , 2015, International journal of cancer.

[166]  R. V. van Etten,et al.  P210 and P190BCR/ABL Induce the Tyrosine Phosphorylation and DNA Binding Activity of Multiple Specific STAT Family Members* , 1996, The Journal of Biological Chemistry.

[167]  Jiayuh Lin,et al.  Signal transducer and activator of transcription 3 activation is associated with bladder cancer cell growth and survival , 2008, Molecular Cancer.

[168]  Benjamin E. Gross,et al.  The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. , 2012, Cancer discovery.

[169]  Hua Tang,et al.  An oligonucleotide decoy for Stat3 activates the immune response of macrophages to breast cancer. , 2006, Immunobiology.

[170]  K. Yasukawa,et al.  Human soluble IL-6 receptor: its detection and enhanced release by HIV infection. , 1992, Journal of immunology.

[171]  Q. Cai,et al.  Serum-resistant CpG-STAT3 decoy for targeting survival and immune checkpoint signaling in acute myeloid leukemia. , 2016, Blood.

[172]  P. Campbell,et al.  Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders , 2005, The Lancet.

[173]  G. Wolf,et al.  Interleukin‐6 predicts recurrence and survival among head and neck cancer patients , 2008, Cancer.

[174]  Miao-Fen Chen,et al.  IL-6 expression predicts treatment response and outcome in squamous cell carcinoma of the esophagus , 2013, Molecular Cancer.

[175]  R. Figlin,et al.  Microenvironment and Immunology Targeting Stat3 in the Myeloid Compartment Drastically Improves the in Vivo Antitumor Functions of Adoptively Transferred T Cells , 2022 .

[176]  P. Galle,et al.  IL-6 Receptor Independent Stimulation of Human gp130 by Viral IL-61 , 2000, The Journal of Immunology.

[177]  J. Nemunaitis,et al.  AZD9150, a next-generation antisense oligonucleotide inhibitor of STAT3 with early evidence of clinical activity in lymphoma and lung cancer , 2015, Science Translational Medicine.

[178]  J. Dipersio,et al.  The clinical benefit of ruxolitinib across patient subgroups: analysis of a placebo‐controlled, Phase III study in patients with myelofibrosis , 2013, British journal of haematology.

[179]  J. Smolen,et al.  Rapid and sustained improvement in bone and cartilage turnover markers with the anti-interleukin-6 receptor inhibitor tocilizumab plus methotrexate in rheumatoid arthritis patients with an inadequate response to methotrexate: results from a substudy of the multicenter double-blind, placebo-controlle , 2010, Arthritis and rheumatism.

[180]  M. Suarez‐Almazor,et al.  Successful treatment of arthritis induced by checkpoint inhibitors with tocilizumab: a case series , 2017, Annals of the rheumatic diseases.

[181]  Stefan N. Constantinescu,et al.  A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera , 2005, Nature.

[182]  S. Altiok,et al.  Antitumor Efficacy of the Anti-Interleukin-6 (IL-6) Antibody Siltuximab in Mouse Xenograft Models of Lung Cancer , 2014, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[183]  Can Alkan,et al.  Activating mutations of STAT5B and STAT3 in lymphomas derived from γδ-T or NK cells , 2015, Nature Communications.

[184]  R. Figlin,et al.  Targeting STAT3 in adoptively transferred T cells promotes their in vivo expansion and antitumor effects. , 2010, Cancer research.

[185]  M. Griesshammer,et al.  Ruxolitinib for the treatment of inadequately controlled polycythaemia vera without splenomegaly (RESPONSE-2): a randomised, open-label, phase 3b study. , 2017, The Lancet. Oncology.

[186]  B. Clotet,et al.  Once-daily dolutegravir versus darunavir plus ritonavir for treatment-naive adults with HIV-1 infection (FLAMINGO): 96 week results from a randomised, open-label, phase 3b study. , 2015, The lancet. HIV.

[187]  T. Taniguchi,et al.  Complementary DNA for a novel human interleukin (BSF-2) that induces B lymphocytes to produce immunoglobulin , 1986, Nature.

[188]  Y. Dou,et al.  IL-22(+)CD4(+) T cells promote colorectal cancer stemness via STAT3 transcription factor activation and induction of the methyltransferase DOT1L. , 2014, Immunity.

[189]  Jih-Hsiang Lee,et al.  The Janus Kinases Inhibitor AZD1480 Attenuates Growth of Small Cell Lung Cancers In Vitro and In Vivo , 2013, Clinical Cancer Research.

[190]  M. Moriyama,et al.  Increased expression of interleukin-6 predicts poor response to chemoradiotherapy and unfavorable prognosis in oral squamous cell carcinoma , 2015, Oncology reports.

[191]  W. Gerald,et al.  Mutations in the EGFR kinase domain mediate STAT3 activation via IL-6 production in human lung adenocarcinomas. , 2007, The Journal of clinical investigation.

[192]  Q. Lv,et al.  STAT3, a Poor Survival Predicator, Is Associated with Lymph Node Metastasis from Breast Cancer , 2013, Journal of breast cancer.

[193]  Bianca Sperl,et al.  Stattic: a small-molecule inhibitor of STAT3 activation and dimerization. , 2006, Chemistry & biology.

[194]  D. Leino,et al.  Severe cytokine release syndrome in a patient receiving PD‐1‐directed therapy , 2017, Pediatric blood & cancer.

[195]  B. Goh,et al.  Do STAT3 inhibitors have potential in the future for cancer therapy? , 2017, Expert opinion on investigational drugs.

[196]  S. Katz,et al.  Tumor-associated GM-CSF overexpression induces immunoinhibitory molecules via STAT3 in myeloid-suppressor cells infiltrating liver metastases , 2016, Cancer Gene Therapy.

[197]  S. Aaronson,et al.  Implications for Cancer Therapy , 2003 .

[198]  J. Scheller,et al.  Interleukin‐6 biology is coordinated by membrane‐bound and soluble receptors: role in inflammation and cancer , 2006, Journal of leukocyte biology.

[199]  Juan Hidalgo,et al.  Trans-Signaling Is a Dominant Mechanism for the Pathogenic Actions of Interleukin-6 in the Brain , 2014, The Journal of Neuroscience.

[200]  W. Vainchenker,et al.  Faculty of 1000 evaluation for Randomized, Double-Blind, Phase II Study of Ruxolitinib or Placebo in Combination With Capecitabine in Patients With Metastatic Pancreatic Cancer for Whom Therapy With Gemcitabine Has Failed. , 2018 .

[201]  The role of STAT-3 in the induction of apoptosis in pancreatic cancer cells by benzyl isothiocyanate. , 2009, Journal of the National Cancer Institute.

[202]  H. Ludwig,et al.  Interleukin-6 is a prognostic factor in multiple myeloma. , 1991, Blood.

[203]  Michael L. Wang,et al.  Blockade of interleukin‐6 signalling with siltuximab enhances melphalan cytotoxicity in preclinical models of multiple myeloma , 2011, British journal of haematology.

[204]  J. Pinski,et al.  Clinical and Correlative Results of SWOG S0354: A Phase II Trial of CNTO328 (Siltuximab), a Monoclonal Antibody against Interleukin-6, in Chemotherapy-Pretreated Patients with Castration-Resistant Prostate Cancer , 2010, Clinical Cancer Research.

[205]  Jie Shen,et al.  Inhibitory effects of decoy-ODN targeting activated STAT3 on human glioma growth in vivo. , 2009, In vivo.

[206]  Y. Fujisawa,et al.  Serum level of interleukin-6 is increased in nivolumab-associated psoriasiform dermatitis and tumor necrosis factor-α is a biomarker of nivolumab recativity. , 2017, Journal of dermatological science.

[207]  E. Laurini,et al.  Hitting the right spot: Mechanism of action of OPB‐31121, a novel and potent inhibitor of the Signal Transducer and Activator of Transcription 3 (STAT3) , 2015, Molecular oncology.

[208]  Y. Suh,et al.  Inhibition of IL-6/STAT3 axis and targeting Axl and Tyro3 receptor tyrosine kinases by apigenin circumvent taxol resistance in ovarian cancer cells. , 2015, International journal of oncology.

[209]  Rong Li,et al.  Interleukin 6 Secreted from Adipose Stromal Cells Promotes Migration and Invasion of Breast Cancer Cells , 2009, Oncogene.

[210]  Hua Yu,et al.  The STATs of cancer — new molecular targets come of age , 2004, Nature Reviews Cancer.

[211]  Hua Yu,et al.  The JAK2 inhibitor AZD1480 potently blocks Stat3 signaling and oncogenesis in solid tumors. , 2009, Cancer cell.

[212]  A. Kulkarni,et al.  STAT3 Induces Immunosuppression by Upregulating PD-1/PD-L1 in HNSCC , 2017, Journal of dental research.

[213]  M. Taniwaki,et al.  Phase 1 study in Japan of siltuximab, an anti-IL-6 monoclonal antibody, in relapsed/refractory multiple myeloma , 2015, International Journal of Hematology.

[214]  Chien-Jen Chen,et al.  Circulating interleukin‐6 level is a prognostic marker for survival in advanced nonsmall cell lung cancer patients treated with chemotherapy , 2013, International journal of cancer.

[215]  E. Lee,et al.  Tofacitinib or adalimumab versus placebo in rheumatoid arthritis. , 2012, The New England journal of medicine.

[216]  Lin Li,et al.  Whole-genome sequencing identifies recurrent mutations in hepatocellular carcinoma , 2013, Genome research.

[217]  A. Cumano,et al.  Jak2 Deficiency Defines an EssentialDevelopmental Checkpoint in DefinitiveHematopoiesis , 1998, Cell.

[218]  Kenji Matsuno,et al.  Identification of a New Series of STAT3 Inhibitors by Virtual Screening. , 2010, ACS medicinal chemistry letters.

[219]  N. Yanaihara,et al.  Antitumor effects of interleukin‐6 (IL‐6)/interleukin‐6 receptor (IL‐6R) signaling pathway inhibition in clear cell carcinoma of the ovary , 2016, Molecular carcinogenesis.

[220]  Jun Shen,et al.  IL-6 and PD-L1 blockade combination inhibits hepatocellular carcinoma cancer development in mouse model. , 2017, Biochemical and biophysical research communications.

[221]  C. Hunter,et al.  IL-6 as a keystone cytokine in health and disease , 2015, Nature Immunology.

[222]  T. Barbui,et al.  Erratum: Long-term findings from COMFORT-II, a phase 3 study of ruxolitinib vs best available therapy for myelofibrosis , 2017, Leukemia.

[223]  C. Burns,et al.  Targeting JAK kinase in solid tumors: emerging opportunities and challenges , 2016, Oncogene.

[224]  K. Takeda,et al.  Enhanced Cancer Immunotherapy Using STAT3-Depleted Dendritic Cells with High Th1-Inducing Ability and Resistance to Cancer Cell-Derived Inhibitory Factors , 2011, The Journal of Immunology.

[225]  長﨑 高也.  Interleukin-6 released by colon cancer-associated fibroblasts is critical for tumour angiogenesis : anti-interleukin-6 receptor antibody suppressed angiogenesis and inhibited tumour-stroma interaction , 2014 .

[226]  Xiaolei Zhang,et al.  Inhibitory effects of STAT3 decoy oligodeoxynucleotides on human epithelial ovarian cancer cell growth in vivo. , 2013, International journal of molecular medicine.

[227]  J. D. Clark,et al.  The mechanism of action of tofacitinib - an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis. , 2016, Clinical and experimental rheumatology.

[228]  G. Kollias,et al.  Interleukin 6 Is Required for the Development of Collagen-induced Arthritis , 1998, The Journal of experimental medicine.

[229]  C. Liu,et al.  Bypassing STAT3-mediated inhibition of the transcriptional regulator ID2 improves the antitumor efficacy of dendritic cells , 2016, Science Signaling.

[230]  Karl Hörmann,et al.  Serum levels of interleukin-6 in patients with primary head and neck squamous cell carcinoma. , 2005, Anticancer research.

[231]  Z. Tian,et al.  Therapeutic effects of STAT3 decoy oligodeoxynucleotide on human lung cancer in xenograft mice , 2007, BMC Cancer.

[232]  M. Karin,et al.  IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer. , 2009, Cancer cell.

[233]  Yuan Zhang,et al.  Both miR-17-5p and miR-20a Alleviate Suppressive Potential of Myeloid-Derived Suppressor Cells by Modulating STAT3 Expression , 2011, The Journal of Immunology.

[234]  S. Vermeire,et al.  Tofacitinib for induction and maintenance therapy of Crohn's disease: results of two phase IIb randomised placebo-controlled trials , 2017, Gut.

[235]  D. Hori,et al.  Expression of activated signal transducer and activator of transcription-3 predicts poor prognosis in cervical squamous-cell carcinoma , 2009, British Journal of Cancer.

[236]  Michael L. Wang,et al.  Siltuximab (CNTO 328) with lenalidomide, bortezomib and dexamethasone in newly-diagnosed, previously untreated multiple myeloma: an open-label phase I trial , 2016, Blood Cancer Journal.

[237]  O. Cummings,et al.  Activation of the signal transducers and activators of the transcription 3 pathway in alveolar epithelial cells induces inflammation and adenocarcinomas in mouse lung. , 2007, Cancer research.

[238]  E. Plimack,et al.  AZD1480: a phase I study of a novel JAK2 inhibitor in solid tumors. , 2013, The oncologist.

[239]  Yuan‐Chang Chung,et al.  Serum interleukin‐6 levels reflect the disease status of colorectal cancer , 2003, Journal of surgical oncology.

[240]  Hua Yu,et al.  Regulation of the innate and adaptive immune responses by Stat-3 signaling in tumor cells , 2004, Nature Medicine.

[241]  Benjamin E. Gross,et al.  Integrative Analysis of Complex Cancer Genomics and Clinical Profiles Using the cBioPortal , 2013, Science Signaling.

[242]  E. Mohammadi,et al.  Barriers and facilitators related to the implementation of a physiological track and trigger system: A systematic review of the qualitative evidence , 2017, International journal for quality in health care : journal of the International Society for Quality in Health Care.

[243]  S. Mustjoki,et al.  Somatic STAT3 mutations in large granular lymphocytic leukemia. , 2012, The New England journal of medicine.

[244]  Hua Yu,et al.  Cutting Edge: An In Vivo Requirement for STAT3 Signaling in TH17 Development and TH17-Dependent Autoimmunity1 , 2007, The Journal of Immunology.

[245]  J. Bono,et al.  Randomised phase II study of siltuximab (CNTO 328), an anti-IL-6 monoclonal antibody, in combination with mitoxantrone/prednisone versus mitoxantrone/prednisone alone in metastatic castration-resistant prostate cancer. , 2012, European journal of cancer.

[246]  N. Zhang,et al.  The EGFR pathway is involved in the regulation of PD-L1 expression via the IL-6/JAK/STAT3 signaling pathway in EGFR-mutated non-small cell lung cancer. , 2016, International journal of oncology.

[247]  Simion I. Chiosea,et al.  JAK Kinase Inhibition Abrogates STAT3 Activation and Head and Neck Squamous Cell Carcinoma Tumor Growth12 , 2015, Neoplasia.

[248]  Shizuo Akira,et al.  Stat3/Socs3 activation by IL-6 transsignaling promotes progression of pancreatic intraepithelial neoplasia and development of pancreatic cancer. , 2011, Cancer cell.

[249]  Simon A. Jones,et al.  The biology behind interleukin-6 targeted interventions , 2016, Current opinion in rheumatology.

[250]  Jens Schneider-Mergener,et al.  Differential Activation of Acute Phase Response Factor/STAT3 and STAT1 via the Cytoplasmic Domain of the Interleukin 6 Signal Transducer gp130 , 1996, The Journal of Biological Chemistry.

[251]  P. Russell,et al.  IL6 Trans-signaling Promotes KRAS-Driven Lung Carcinogenesis. , 2016, Cancer research.

[252]  J. Datta,et al.  IL-6 Promotes Head and Neck Tumor Metastasis by Inducing Epithelial–Mesenchymal Transition via the JAK-STAT3-SNAIL Signaling Pathway , 2011, Molecular Cancer Research.

[253]  E. Galun,et al.  Tissue microarray-based study of patients with lymph node-positive breast cancer shows tyrosine phosphorylation of signal transducer and activator of transcription 3 (tyrosine705-STAT3) is a marker of good prognosis , 2012, Clinical and Translational Oncology.

[254]  S. Holland,et al.  A critical role for STAT3 transcription factor signaling in the development and maintenance of human T cell memory. , 2011, Immunity.

[255]  P. Sharma,et al.  Selective inhibition of autoimmune exacerbation while preserving the anti-tumor clinical benefit using IL-6 blockade in a patient with advanced melanoma and Crohn’s disease: a case report , 2016, Journal of Hematology & Oncology.

[256]  J. Davis,et al.  Interleukin-6 and cachexia in ApcMin/+ mice. , 2008, American journal of physiology. Regulatory, integrative and comparative physiology.

[257]  R. Moriggl,et al.  Both STAT1 and STAT3 are favourable prognostic determinants in colorectal carcinoma , 2013, British Journal of Cancer.

[258]  S. Lonial,et al.  Siltuximab, a novel anti-interleukin-6 monoclonal antibody, for Castleman's disease. , 2010, Journal of Clinical Oncology.

[259]  Miao-Fen Chen,et al.  The role of IL-6 in the radiation response of prostate cancer , 2013, Radiation oncology.

[260]  Johannes Zuber,et al.  Disruption of STAT3 signalling promotes KRAS-induced lung tumorigenesis , 2015, Nature Communications.

[261]  A. Heimberger,et al.  A novel small molecule inhibitor of signal transducers and activators of transcription 3 reverses immune tolerance in malignant glioma patients. , 2007, Cancer research.

[262]  J. Darnell,et al.  Stat3 as an Oncogene , 1999, Cell.

[263]  D. Santini,et al.  IL-6 triggers malignant features in mammospheres from human ductal breast carcinoma and normal mammary gland. , 2007, The Journal of clinical investigation.

[264]  S. Akira,et al.  Targeted disruption of the mouse Stat3 gene leads to early embryonic lethality. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[265]  J. Licht,et al.  Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia , 2003, Nature Genetics.

[266]  R. Dhir.  Stat3 Promotes Metastatic Progression of Prostate Cancer , 2009 .