The IL-6 feed-forward loop: A driver of tumorigenesis

Seminars in Immunology

Volumn 26, Issue 1, 2014, Pages 48-53

  Chang, Qing ^a   Daly, Laura ^a   Bromberg, Jacqueline ^a,b  

^a MEMORIAL SLOAN KETTERING CANCER CENTER   (United States)

^b WEILL CORNELL MEDICAL COLLEGE   (United States)

Author keywords

Cancer; Metastasis; Microenvironment

Indexed keywords

ERLOTINIB; INTERLEUKIN 6; SILTUXIMAB; TOCILIZUMAB; TRASTUZUMAB;

ANTINEOPLASTIC ACTIVITY; CARCINOGENESIS; CELLULAR DISTRIBUTION; HUMAN; METASTASIS; MOLECULAR MECHANICS; NONHUMAN; PROTEIN FUNCTION; REVIEW; SIGNAL TRANSDUCTION; TUMOR GROWTH; TUMOR MICROENVIRONMENT;

CANCER; METASTASIS; MICROENVIRONMENT;

ANIMALS; CELL TRANSFORMATION, NEOPLASTIC; HUMANS; INTERLEUKIN-6; MOLECULAR TARGETED THERAPY; NEOPLASMS; RECEPTORS, INTERLEUKIN-6; SIGNAL TRANSDUCTION;

EID: 84896491618     PISSN: 10445323     EISSN: 10963618     Source Type: Journal    
DOI: 10.1016/j.smim.2014.01.007     Document Type: Review

References (123)

1. Sansone P., Bromberg J. Targeting the interleukin-6/Jak/stat pathway in human malignancies. Clinical Oncology: Official Journal of the American Society of Clinical Oncology 2012, 30(March (9)):1005-1014.
2. Kasama T., Isojima S., Umemura M., Tsukamoto H., Tokunaga T., Furuya H., et al. Serum macrophage migration inhibitory factor levels are correlated with response to tocilizumab therapy in patients with rheumatoid arthritis. Rheumatology International 2013.
3. Shimamoto K., Ito T., Ozaki Y., Amuro H., Tanaka A., Nishizawa T., et al. Serum interleukin 6 before and after therapy with tocilizumab is a principal biomarker in patients with rheumatoid arthritis. Journal of Rheumatology 2013, 40:1074-1081.
4. Woo P., Humphries S.E. IL-6 polymorphisms: a useful genetic tool for inflammation research?. Journal of Clinical Investigation 2013, 123:1413-1414.
5. Kim S., Hagemann A., DeMichele A. Immuno-modulatory gene polymorphisms and outcome in breast and ovarian cancer. Immunological Investigations 2009, 38:324-340.
6. Gao S.P., Mark K.G., Leslie K., Pao W., Motoi N., Gerald W.L., et al. Mutations in the EGFR kinase domain mediate STAT3 activation via IL-6 production in human lung adenocarcinomas. Journal of Clinical Investigation 2007, 117:3846-3856.
7. Schafer Z.T., Brugge J.S. IL-6 involvement in epithelial cancers. Journal of Clinical Investigation 2007, 117:3660-3663.
8. Hartman Z.C., Yang X.Y., Glass O., Lei G., Osada T., Dave S.S., et al. HER2 overexpression elicits a proinflammatory IL-6 autocrine signaling loop that is critical for tumorigenesis. Cancer Research 2011, 71:4380-4391.
9. Langkamp-Henken B., Wood S.M., Herlinger-Garcia K.A., Thomas D.J., Stechmiller J.K., Bender B.S., et al. Nutritional formula improved immune profiles of seniors living in nursing homes. Journal of the American Geriatrics Society 2006, 54:1861-1870.
10. Leslie K., Gao S.P., Berishaj M., Podsypanina K., Ho H., Ivashkiv L., et al. Differential interleukin-6/Stat3 signaling as a function of cellular context mediates Ras-induced transformation. Breast Cancer Research: BCR 2010, 12:R80.
11. Ancrile B., Lim K.H., Counter C.M. Oncogenic Ras-induced secretion of IL6 is required for tumorigenesis. Genes & Development 2007, 21:1714-1719.
12. Chou C.H., Wei L.H., Kuo M.L., Huang Y.J., Lai K.P., Chen C.A., et al. Up-regulation of interleukin-6 in human ovarian cancer cell via a Gi/PI3K-Akt/NF-kappaB pathway by lysophosphatidic acid, an ovarian cancer-activating factor. Carcinogenesis 2005, 26:45-52.
13. Dagia N.M., Agarwal G., Kamath D.V., Chetrapal-Kunwar A., Gupte R.D., Jadhav M.G., et al. A preferential p110alpha/gamma PI3K inhibitor attenuates experimental inflammation by suppressing the production of proinflammatory mediators in a NF-kappaB-dependent manner. American Journal of Physiology Cell Physiology 2010, 298:C929-C941.
14. Tapia-Abellan A., Ruiz-Alcaraz A.J., Hernandez-Caselles T., Such J., Frances R., Garcia-Penarrubia P., et al. Role of MAP kinases and PI3K-Akt on the cytokine inflammatory profile of peritoneal macrophages from the ascites of cirrhotic patients. Liver International: Official Journal of the International Association for the Study of the Liver 2013, 33:552-560.
15. Garbers C., Spudy B., Aparicio-Siegmund S., Waetzig G.H., Sommer J., Holscher C., et al. An interleukin-6 receptor-dependent molecular switch mediates signal transduction of the IL-27 cytokine subunit p28 (IL-30) via a gp130 protein receptor homodimer. Journal of Biological Chemistry 2013, 288:4346-4354.
16. Gross V., Zhang B., Geng Y., Villiger P.M., Lotz M. Regulation of interleukin-6 (IL-6) expression: evidence for a tissue-specific role of protein kinase C. Journal of Clinical Immunology 1993, 13:310-320.
17. Karin M. NF-kappaB as a critical link between inflammation and cancer. Cold Spring Harbor Perspectives in Biology 2009, 1:a000141.
18. Spooren A., Kooijman R., Lintermans B., Van Craenenbroeck K., Vermeulen L., Haegeman G., et al. Cooperation of NFkappaB and CREB to induce synergistic IL-6 expression in astrocytes. Cellular Signalling 2010, 22:871-881.
19. Gerlo S., Haegeman G., Vanden Berghe W. Transcriptional regulation of autocrine IL-6 expression in multiple myeloma cells. Cellular Signalling 2008, 20:1489-1496.
20. Matsusaka T., Fujikawa K., Nishio Y., Mukaida N., Matsushima K., Kishimoto T., et al. Transcription factors NF-IL6 and NF-kappa B synergistically activate transcription of the inflammatory cytokines, interleukin 6 and interleukin 8. Proceedings of the National Academy of Sciences of the United States of America 1993, 90:10193-10197.
21. Kishimoto T. Interleukin-6: from basic science to medicine - 40 years in immunology. Annual Review of Immunology 2005, 23:1-21.
22. Grivennikov S., Karin M. Autocrine IL-6 signaling: a key event in tumorigenesis?. Cancer Cell 2008, 13:7-9.
23. Sansone P., Storci G., Tavolari S., Guarnieri T., Giovannini C., Taffurelli M., et al. IL-6 triggers malignant features in mammospheres from human ductal breast carcinoma and normal mammary gland. Journal of Clinical Investigation 2007, 117:3988-4002.
24. Chang Q., Bournazou E., Sansone P., Berishaj M., Gao S.P., Daly L., et al. The IL-6/JAK/Stat3 feed-forward loop drives tumorigenesis and metastasis. Neoplasia 2013, 15:848-862.
25. Yang J., Liao X., Agarwal M.K., Barnes L., Auron P.E., Stark G.R. Unphosphorylated STAT3 accumulates in response to IL-6 and activates transcription by binding to NFkappaB. Genes & Development 2007, 21:1396-1408.
26. Wang Y., van Boxel-Dezaire A.H., Cheon H., Yang J., Stark G.R. STAT3 activation in response to IL-6 is prolonged by the binding of IL-6 receptor to EGF receptor. Proceedings of the National Academy of Sciences of the United States of America 2013, 110:16975-16980.
27. Dry J.R., Pavey S., Pratilas C.A., Harbron C., Runswick S., Hodgson D., et al. Transcriptional pathway signatures predict MEK addiction and response to selumetinib (AZD6244). Cancer Research 2010, 70:2264-2273.
28. Bid H.K., Kibler A., Phelps D.A., Manap S., Xiao L., Lin J., et al. Development, characterization, and reversal of acquired resistance to the MEK1 inhibitor selumetinib (AZD6244) in an in vivo model of childhood astrocytoma. Clinical Cancer Research: An Official Journal of the American Association for Cancer Research 2013.
29. Vultur A., Villanueva J., Krepler C., Rajan G., Chen Q., Xiao M., et al. MEK inhibition affects STAT3 signaling and invasion in human melanoma cell lines. Oncogene 2013.
30. Krasilnikov M., Ivanov V.N., Dong J., Ronai Z. ERK and PI3K negatively regulate STAT-transcriptional activities in human melanoma cells: implications towards sensitization to apoptosis. Oncogene 2003, 22:4092-4101.
31. Lodge P., McWhir J., Gallagher E., Sang H. Increased gp130 signaling in combination with inhibition of the MEK/ERK pathway facilitates embryonic stem cell isolation from normally refractory murine CBA blastocysts. Cloning and Stem Cells 2005, 7:2-7.
32. Radtke S., Wuller S., Yang X.P., Lippok B.E., Mutze B., Mais C., et al. Cross-regulation of cytokine signalling: pro-inflammatory cytokines restrict IL-6 signalling through receptor internalisation and degradation. Journal of Cell Science 2010, 123:947-959.
33. Dittrich E., Haft C.R., Muys L., Heinrich P.C., Graeve L. A di-leucine motif and an upstream serine in the interleukin-6 (IL-6) signal transducer gp130 mediate ligand-induced endocytosis and down-regulation of the IL-6 receptor. Journal of Biological Chemistry 1996, 271:5487-5494.
34. Dittrich E., Rose-John S., Gerhartz C., Mullberg J., Stoyan T., Yasukawa K., et al. Identification of a region within the cytoplasmic domain of the interleukin-6 (IL-6) signal transducer gp130 important for ligand-induced endocytosis of the IL-6 receptor. Journal of Biological Chemistry 1994, 269:19014-19020.
35. Schmidt-Arras D., Muller M., Stevanovic M., Horn S., Schutt A., Bergmann J., et al. Oncogenic deletion mutants of gp130 signal from intracellular compartments. Journal of Cell Science 2013.
36. Schutt A., Zacharias M., Schneider N., Horn S., Grotzinger J., Rose-John S., et al. gp130 activation is regulated by D2-D3 interdomain connectivity. Biochemical Journal 2013, 450:487-496.
37. Rebouissou S., Amessou M., Couchy G., Poussin K., Imbeaud S., Pilati C., et al. Frequent in-frame somatic deletions activate gp130 in inflammatory hepatocellular tumours. Nature 2009, 457:200-204.
38. Babon J.J., Nicola N.A. The biology and mechanism of action of suppressor of cytokine signaling 3. Growth Factors 2012, 30:207-219.
39. Balko J.M., Giltnane J.M., Wang K., Schwarz L.J., Young C.D., Cook R.S., et al. Molecular profiling of the residual disease of triple-negative breast cancers after neoadjuvant chemotherapy identifies actionable therapeutic targets. Cancer Discovery 2014.
40. Fidler I.J. The pathogenesis of cancer metastasis: the 'seed and soil' hypothesis revisited. Nature Reviews Cancer 2003, 3:453-458.
41. Reynaud D., Pietras E., Barry-Holson K., Mir A., Binnewies M., Jeanne M., et al. IL-6 controls leukemic multipotent progenitor cell fate and contributes to chronic myelogenous leukemia development. Cancer Cell 2011, 20:661-673.
42. Huang W.H., Chang M.C., Tsai K.S., Hung M.C., Chen H.L., Hung S.C. Mesenchymal stem cells promote growth and angiogenesis of tumors in mice. Oncogene 2013, 32:4343-4354.
43. Hugo H.J., Lebret S., Tomaskovic-Crook E., Ahmed N., Blick T., Newgreen D.F., et al. Contribution of fibroblast and mast cell (afferent) and tumor (efferent) IL-6 effects within the tumor microenvironment. Cancer Microenvironment: Official Journal of the International Cancer Microenvironment Society 2012.
44. Tsai K.S., Yang S.H., Lei Y.P., Tsai C.C., Chen H.W., Hsu C.Y., et al. Mesenchymal stem cells promote formation of colorectal tumors in mice. Gastroenterology 2011, 141:1046-1056.
45. Fierro F.A., Sierralta W.D., Epunan M.J., Minguell J.J. Marrow-derived mesenchymal stem cells: role in epithelial tumor cell determination. Clinical & Experimental Metastasis 2004, 21:313-319.
46. Sethi N., Dai X., Winter C.G., Kang Y. Tumor-derived JAGGED1 promotes osteolytic bone metastasis of breast cancer by engaging notch signaling in bone cells. Cancer Cell 2011, 19:192-205.
47. Chalmin F., Ladoire S., Mignot G., Vincent J., Bruchard M., Remy-Martin J.P., et al. Membrane-associated Hsp72 from tumor-derived exosomes mediates STAT3-dependent immunosuppressive function of mouse and human myeloid-derived suppressor cells. Journal of Clinical Investigation 2010, 120:457-471.
48. Liu Y., Xiang X., Zhuang X., Zhang S., Liu C., Cheng Z., et al. Contribution of MyD88 to the tumor exosome-mediated induction of myeloid derived suppressor cells. American Journal of Pathology 2010, 176:2490-2499.
49. Bretz N.P., Ridinger J., Rupp A.K., Rimbach K., Keller S., Rupp C., et al. Body fluid exosomes promote secretion of inflammatory cytokines in monocytic cells via TLR signaling. Journal of Biological Chemistry 2013.
50. Peinado H., Lavotshkin S., Lyden D. The secreted factors responsible for pre-metastatic niche formation: old sayings and new thoughts. Seminars in Cancer Biology 2011, 21:139-146.
51. Kuilman T., Michaloglou C., Vredeveld L.C., Douma S., van Doorn R., Desmet C.J., et al. Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network. Cell 2008, 133:1019-1031.
52. Lee S.O., Chun J.Y., Nadiminty N., Lou W., Gao A.C. Interleukin-6 undergoes transition from growth inhibitor associated with neuroendocrine differentiation to stimulator accompanied by androgen receptor activation during LNCaP prostate cancer cell progression. Prostate 2007, 67:764-773.
53. Chen L., Shulman L.M., Revel M. IL-6 receptors and sensitivity to growth inhibition by IL-6 in clones of human breast carcinoma cells. Journal of Biological Regulators and Homeostatic Agents 1991, 5:125-136.
54. Kortylewski M., Heinrich P.C., Mackiewicz A., Schniertshauer U., Klingmuller U., Nakajima K., et al. Interleukin-6 and oncostatin M-induced growth inhibition of human A375 melanoma cells is STAT-dependent and involves upregulation of the cyclin-dependent kinase inhibitor p27/Kip1. Oncogene 1999, 18:3742-3753.
55. Badache A., Hynes N.E. Interleukin 6 inhibits proliferation and, in cooperation with an epidermal growth factor receptor autocrine loop, increases migration of T47D breast cancer cells. Cancer Research 2001, 61:383-391.
56. Culig Z., Puhr M. Interleukin-6: a multifunctional targetable cytokine in human prostate cancer. Molecular and Cellular Endocrinology 2012, 360:52-58.
57. D'Anello L., Sansone P., Storci G., Mitrugno V., D'Uva G., Chieco P., et al. Epigenetic control of the basal-like gene expression profile via Interleukin-6 in breast cancer cells. Molecular Cancer 2010, 9:300.
58. Schroeder A., Herrmann A., Cherryholmes G., Kowolik C., Buettner R., Pal S., et al. Loss of androgen receptor expression promotes a stem-like cell phenotype in prostate cancer through STAT3 signaling. Cancer Research 2013.
59. Lee H., Zhang P., Herrmann A., Yang C., Xin H., Wang Z., et al. Acetylated STAT3 is crucial for methylation of tumor-suppressor gene promoters and inhibition by resveratrol results in demethylation. Proceedings of the National Academy of Sciences of the United States of America 2012, 109:7765-7769.
60. Studebaker A.W., Storci G., Werbeck J.L., Sansone P., Sasser A.K., Tavolari S., et al. Fibroblasts isolated from common sites of breast cancer metastasis enhance cancer cell growth rates and invasiveness in an interleukin-6-dependent manner. Cancer Research 2008, 68:9087-9095.
61. Dethlefsen C., Hojfeldt G., Hojman P. The role of intratumoral and systemic IL-6 in breast cancer. Breast Cancer Research and Treatment 2013, 138:657-664.
62. He G., Dhar D., Nakagawa H., Font-Burgada J., Ogata H., Jiang Y., et al. Identification of liver cancer progenitors whose malignant progression depends on autocrine IL-6 signaling. Cell 2013, 155:384-396.
63. Iliopoulos D., Hirsch H.A., Wang G., Struhl K. Inducible formation of breast cancer stem cells and their dynamic equilibrium with non-stem cancer cells via IL6 secretion. Proceedings of the National Academy of Sciences of the United States of America 2011, 108:1397-1402.
64. Korkaya H., Kim G.I., Davis A., Malik F., Henry N.L., Ithimakin S., et al. Activation of an IL6 inflammatory loop mediates trastuzumab resistance in HER2+ breast cancer by expanding the cancer stem cell population. Molecular Cell 2012, 47:570-584.
65. Wang Y., Qu Y., Zhang X.L., Xing J., Niu X.L., Chen X., et al. Autocrine production of interleukin-6 confers ovarian cancer cells resistance to tamoxifen via ER isoforms and SRC-1. Molecular and Cellular Endocrinology 2013, 382:791-803.
66. Quante M., Tu S.P., Tomita H., Gonda T., Wang S.S., Takashi S., et al. Bone marrow-derived myofibroblasts contribute to the mesenchymal stem cell niche and promote tumor growth. Cancer Cell 2011, 19:257-272.
67. Yi H., Cho H.J., Cho S.M., Jo K., Park J.A., Kim N.H., et al. Blockade of interleukin-6 receptor suppresses the proliferation of H460 lung cancer stem cells. International Journal of Oncology 2012, 41:310-316.
68. Marotta L.L., Almendro V., Marusyk A., Shipitsin M., Schemme J., Walker S.R., et al. The JAK2/STAT3 signaling pathway is required for growth of CD44(+)CD24(-) stem cell-like breast cancer cells in human tumors. Journal of Clinical Investigation 2011, 121:2723-2735.
69. Douglas A.M., Goss G.A., Sutherland R.L., Hilton D.J., Berndt M.C., Nicola N.A., et al. Expression and function of members of the cytokine receptor superfamily on breast cancer cells. Oncogene 1997, 14:661-669.
70. Tamm I., Cardinale I., Kikuchi T., Krueger J.G. E-cadherin distribution in interleukin 6-induced cell-cell separation of ductal breast carcinoma cells. Proceedings of the National Academy of Sciences of the United States of America 1994, 91:4338-4342.
71. Tamm I., Kikuchi T., Cardinale I., Krueger J.G. Cell-adhesion-disrupting action of interleukin 6 in human ductal breast carcinoma cells. Proceedings of the National Academy of Sciences of the United States of America 1994, 91:3329-3333.
72. Kim M.Y., Oskarsson T., Acharyya S., Nguyen D.X., Zhang X.H., Norton L., et al. Tumor self-seeding by circulating cancer cells. Cell 2009, 139:1315-1326.
73. Bao B., Ali S., Ahmad A., Azmi A.S., Li Y., Banerjee S., et al. Hypoxia-induced aggressiveness of pancreatic cancer cells is due to increased expression of VEGF, IL-6 and miR-21, which can be attenuated by CDF treatment. PLoS ONE 2012, 7:e50165.
74. Bao B., Ahmad A., Kong D., Ali S., Azmi A.S., Li Y., et al. Hypoxia induced aggressiveness of prostate cancer cells is linked with deregulated expression of VEGF, IL-6 and miRNAs that are attenuated by CDF. PLoS ONE 2012, 7:e43726.
75. Matsui H., Ihara Y., Fujio Y., Kunisada K., Akira S., Kishimoto T., et al. Induction of interleukin (IL)-6 by hypoxia is mediated by nuclear factor (NF)-kappa B and NF-IL6 in cardiac myocytes. Cardiovascular Research 1999, 42:104-112.
76. Qu Y., Oyan A.M., Liu R., Hua Y., Zhang J., Hovland R., et al. Generation of prostate tumor-initiating cells is associated with elevation of reactive oxygen species and IL-6/STAT3 signaling. Cancer Research 2013, 73:7090-7100.
77. Catalano V., Turdo A., Di Franco S., Dieli F., Todaro M., Stassi G. Tumor and its microenvironment: a synergistic interplay. Seminars in Cancer Biology 2013, 23:522-532.
78. Oh K., Lee O.Y., Shon S.Y., Nam O., Ryu P.M., Seo M.W., et al. A mutual activation loop between breast cancer cells and myeloid-derived suppressor cells facilitates spontaneous metastasis through IL-6 trans-signaling in a murine model. Breast Cancer Research: BCR 2013, 15:R79.
79. Lee H., Deng J., Kujawski M., Yang C., Liu Y., Herrmann A., et al. STAT3-induced S1PR1 expression is crucial for persistent STAT3 activation in tumors. Nature Medicine 2010, 16:1421-1428.
80. Man S., Munoz R., Kerbel R.S. On the development of models in mice of advanced visceral metastatic disease for anti-cancer drug testing. Cancer Metastasis Reviews 2007, 26:737-747.
81. Karnoub A.E., Dash A.B., Vo A.P., Sullivan A., Brooks M.W., Bell G.W., et al. Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature 2007, 449:557-563.
82. Pardoll D.M. The blockade of immune checkpoints in cancer immunotherapy. Nature Reviews Cancer 2012, 12:252-264.
83. Menetrier-Caux C., Montmain G., Dieu M.C., Bain C., Favrot M.C., Caux C., et al. Inhibition of the differentiation of dendritic cells from CD34(+) progenitors by tumor cells: role of interleukin-6 and macrophage colony-stimulating factor. Blood 1998, 92:4778-4791.
84. Chomarat P., Banchereau J., Davoust J., Palucka A.K. IL-6 switches the differentiation of monocytes from dendritic cells to macrophages. Nature Immunology 2000, 1:510-514.
85. Roca H., Varsos Z.S., Sud S., Craig M.J., Ying C., Pienta K.J. CCL2 and interleukin-6 promote survival of human CD11b+ peripheral blood mononuclear cells and induce M2-type macrophage polarization. Journal of Biological Chemistry 2009, 284:34342-34354.
86. Wang L., Yi T., Kortylewski M., Pardoll D.M., Zeng D., Yu H. IL-17 can promote tumor growth through an IL-6-Stat3 signaling pathway. Journal of Experimental Medicine 2009, 206:1457-1464.
87. Sumida K., Wakita D., Narita Y., Masuko K., Terada S., Watanabe K., et al. Anti-IL-6 receptor mAb eliminates myeloid-derived suppressor cells and inhibits tumor growth by enhancing T-cell responses. European Journal of Immunology 2012, 42:2060-2072.
88. Gabrilovich D.I., Nagaraj S. Myeloid-derived suppressor cells as regulators of the immune system. Nature Reviews Immunology 2009, 9:162-174.
89. Kujawski M., Kortylewski M., Lee H., Herrmann A., Kay H., Yu H. Stat3 mediates myeloid cell-dependent tumor angiogenesis in mice. Journal of Clinical Investigation 2008, 118:3367-3377.
90. Smith C., Chang M.Y., Parker K.H., Beury D.W., Duhadaway J.B., Flick H.E., et al. IDO is a nodal pathogenic driver of lung cancer and metastasis development. Cancer Discovery 2012, 2:722-735.
91. Monu N.R., Frey A.B. Myeloid-derived suppressor cells and anti-tumor T cells: a complex relationship. Immunological Investigations 2012, 41:595-613.
92. Deng J., Liu Y., Lee H., Herrmann A., Zhang W., Zhang C., et al. S1PR1-STAT3 signaling is crucial for myeloid cell colonization at future metastatic sites. Cancer Cell 2012, 21:642-654.
93. Grivennikov S., Karin E., Terzic J., Mucida D., Yu G.Y., Vallabhapurapu S., et al. IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer. Cancer Cell 2009, 15:103-113.
94. Zhang Y., Yan W., Collins M.A., Bednar F., Rakshit S., Zetter B.R., et al. Interleukin-6 is required for pancreatic cancer progression by promoting MAPK signaling activation and oxidative stress resistance. Cancer Research 2013, 73:6359-6374.
95. Sung S.Y., Liao C.H., Wu H.P., Hsiao W.C., Wu I.H., Jinpu, et al. Loss of let-7 microRNA upregulates IL-6 in bone marrow-derived mesenchymal stem cells triggering a reactive stromal response to prostate cancer. PLoS ONE 2013, 8:e71637.
96. Gentile M., Recchia A.G., Mazzone C., Lucia E., Vigna E., Morabito F. Perspectives in the treatment of multiple myeloma. Expert Opinion on Biological Therapy 2013, 13(Suppl. 1):S1-S22.
97. Kurzrock R., Voorhees P.M., Casper C., Furman R.R., Fayad L., Lonial S., 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. Clinical Cancer Research: An Official Journal of the American Association for Cancer Research 2013, 19:3659-3670.
98. Voorhees P.M., Manges R.F., Sonneveld P., Jagannath S., Somlo G., Krishnan A., et al. A phase 2 multicentre study of siltuximab, an anti-interleukin-6 monoclonal antibody, in patients with relapsed or refractory multiple myeloma. British Journal of Haematology 2013, 161:357-366.
99. Hudes G., Tagawa S.T., Whang Y.E., Qi M., Qin X., Puchalski T.A., et al. A phase 1 study of a chimeric monoclonal antibody against interleukin-6, siltuximab, combined with docetaxel in patients with metastatic castration-resistant prostate cancer. Investigational New Drugs 2013, 31:669-676.
100. Moreau P. The future of therapy for relapsed/refractory multiple myeloma: emerging agents and novel treatment strategies. Seminars in Hematology 2012, 49(Suppl. 1):S33-S46.
101. Fizazi K., De Bono J.S., Flechon A., Heidenreich A., Voog E., Davis N.B., 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. European Journal of Cancer 2012, 48:85-93.
102. Coward J., Kulbe H., Chakravarty P., Leader D., Vassileva V., Leinster D.A., et al. Interleukin-6 as a therapeutic target in human ovarian cancer. Clinical Cancer Research: An Official Journal of the American Association for Cancer Research 2011, 17:6083-6096.
103. Hunsucker S.A., Magarotto V., Kuhn D.J., Kornblau S.M., Wang M., Weber D.M., et al. Blockade of interleukin-6 signalling with siltuximab enhances melphalan cytotoxicity in preclinical models of multiple myeloma. British Journal of Haematology 2011, 152:579-592.
104. Rossi J.F., Negrier S., James N.D., Kocak I., Hawkins R., Davis H., et al. A phase I/II study of siltuximab (CNTO 328), an anti-interleukin-6 monoclonal antibody, in metastatic renal cell cancer. British Journal of Cancer 2010, 103:1154-1162.
105. Guo Y., Nemeth J., O'Brien C., Susa M., Liu X., Zhang Z., et al. Effects of siltuximab on the IL-6-induced signaling pathway in ovarian cancer. Clinical Cancer Research: An Official Journal of the American Association for Cancer Research 2010, 16:5759-5769.
106. van Rhee F., Fayad L., Voorhees P., Furman R., Lonial S., Borghaei H., et al. Siltuximab, a novel anti-interleukin-6 monoclonal antibody, for Castleman's disease. Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology 2010, 28:3701-3708.
107. Li J., Hu X.F., Xing P.X. CNTO-328 (Centocor). Current Opinion on Investigational Drugs 2005, 6:639-645.
108. Nagaraj S., Youn J.I., Weber H., Iclozan C., Lu L., Cotter M.J., et al. Anti-inflammatory triterpenoid blocks immune suppressive function of MDSCs and improves immune response in cancer. Clinical Cancer Research: An Official Journal of the American Association for Cancer Research 2010, 16:1812-1823.
109. Annels N.E., Shaw V.E., Gabitass R.F., Billingham L., Corrie P., Eatock M., et al. The effects of gemcitabine and capecitabine combination chemotherapy and of low-dose adjuvant GM-CSF on the levels of myeloid-derived suppressor cells in patients with advanced pancreatic cancer. Cancer Immunology, Immunotherapy: CII 2013.
110. Sawant A., Schafer C.C., Jin T.H., Zmijewski J., Tse H.M., Roth J., et al. Enhancement of antitumor immunity in lung cancer by targeting myeloid-derived suppressor cell pathways. Cancer Research 2013, 73:6609-6620.
111. Mundy-Bosse B.L., Lesinski G.B., Jaime-Ramirez A.C., Benninger K., Khan M., Kuppusamy P., et al. Myeloid-derived suppressor cell inhibition of the IFN response in tumor-bearing mice. Cancer Research 2011, 71:5101-5110.
112. Le H.K., Graham L., Cha E., Morales J.K., Manjili M.H., Bear H.D. Gemcitabine directly inhibits myeloid derived suppressor cells in BALB/c mice bearing 4T1 mammary carcinoma and augments expansion of T cells from tumor-bearing mice. International Immunopharmacology 2009, 9:900-909.
113. Sinha P., Clements V.K., Bunt S.K., Albelda S.M., Ostrand-Rosenberg S. Cross-talk between myeloid-derived suppressor cells and macrophages subverts tumor immunity toward a type 2 response. Journal of Immunology 2007, 179:977-983.
114. Vincent J., Mignot G., Chalmin F., Ladoire S., Bruchard M., Chevriaux A., et al. 5-Fluorouracil selectively kills tumor-associated myeloid-derived suppressor cells resulting in enhanced T cell-dependent antitumor immunity. Cancer Research 2010, 70:3052-3061.
115. Song L., Rawal B., Nemeth J.A., Haura E.B. JAK1 activates STAT3 activity in non-small-cell lung cancer cells and IL-6 neutralizing antibodies can suppress JAK1-STAT3 signaling. Molecular Cancer Therapeutics 2011, 10:481-494.
116. Korkaya H., Liu S., Wicha M.S. Regulation of cancer stem cells by cytokine networks: attacking cancer's inflammatory roots. Clinical Cancer Research: An Official Journal of the American Association for Cancer Research 2011, 17:6125-6129.
117. Stamell E.F., Wolchok J.D., Gnjatic S., Lee N.Y., Brownell I. The abscopal effect associated with a systemic anti-melanoma immune response. International Journal of Radiation Oncology, Biology, Physics 2013, 85:293-295.
118. Chari A., Pri-Chen H., Jagannath S. Complete remission achieved with single agent CNTO 328, an anti-IL-6 monoclonal antibody, in relapsed and refractory myeloma. Clinical Lymphoma, Myeloma & Leukemia 2013, 13:333-337.
119. Wallenius V., Wallenius K., Ahren B., Rudling M., Carlsten H., Dickson S.L., et al. Interleukin-6-deficient mice develop mature-onset obesity. Nature Medicine 2002, 8:75-79.
120. Kojima T., Yabe Y., Kaneko A., Hirano Y., Ishikawa H., Hayashi M., et al. Monitoring C-reactive protein levels to predict favourable clinical outcomes from tocilizumab treatment in patients with rheumatoid arthritis. Modern Rheumatology/The Japan Rheumatism Association 2013, 23:977-985.
121. Bay-Jensen A.C., Platt A., Byrjalsen I., Vergnoud P., Christiansen C., Karsdal M.A. Effect of tocilizumab combined with methotrexate on circulating biomarkers of synovium, cartilage, and bone in the LITHE study. Seminars in Arthritis and Rheumatism 2013.
122. Bhagwat N., Levine R.L., Koppikar P. Sensitivity and resistance of JAK2 inhibitors to myeloproliferative neoplasms. International Journal of Hematology 2013, 97:695-702.
123. Blanchard J.A., Barve S., Joshi-Barve S., Talwalker R., Gates L.K. Antioxidants inhibit cytokine production and suppress NF-kappaB activation in CAPAN-1 and CAPAN-2 cell lines. Digestive Diseases and Sciences 2001, 46:2768-2772.