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Targeting STAT3 affects melanoma on multiple fronts

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Abstract

As a point of convergence for numerous oncogenic signaling pathways, STAT3 is constitutively-activated at 50 to 90% frequency in diverse human cancers, including melanoma. A critical role of STAT3 in tumor cell survival, proliferation, angiogenesis, metastasis and immune evasion has been recently demonstrated. STAT3 contributes to tumor cell growth by regulating the expression of genes that are involved in cell survival and proliferation. STAT3 promotes metastasis and angiogenesis by inducing expression of the metastatic gene, MMP-2, and the potent angiogenic gene, VEGF. STAT3 participates in the regulation of tumor immune evasion by inhibiting expression of proinflammatory mediators while promoting expression of immune-suppressing factors, which in turn activates STAT3 signaling in dendritic cells leading to immune tolerance. Thus, targeting STAT3 for therapy assaults cancer on multiple fronts. Many of the studies that defined STAT3’s role in oncogenesis were carried out in melanoma cells and tumor models. In this review, we summarize the key role of STAT3 in cancer in general and melanoma in particular. With the emergence of small-molecule drugs that directly inhibit STAT3 or the oncogenic signaling pathways upstream of STAT3 in melanoma, a promising novel approach for melanoma therapy is emerging.

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References

  1. Darnell JE, Jr, Kerr IM, Stark GR: Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science 264: 1415–1421, 1994

    Google Scholar 

  2. Stark GR, Kerr IM, Williams BR, Silverman RH, Schreiber RD: How cells respond to interferons. Annu Rev Biochem 67: 227–264, 1998

    Google Scholar 

  3. Hirano T, Ishihara K, Hibi M: Roles of STAT3 in mediating the cell growth, differentiation and survival signals relayed through the IL-6 family of cytokine receptors. Oncogene 19: 2548–2556, 2000

    Google Scholar 

  4. Heinrich PC, et al.: Principles of interleukin (IL)-6-type cytokine signalling and its regulation. Biochem J 374: 1–20, 2003

    Google Scholar 

  5. Bromberg J, Darnell JE, Jr: The role of STATs in transcriptional control and their impact on cellular function. Oncogene 19: 2468–2473, 2000

    Google Scholar 

  6. Kubo M, Hanada T, Yoshimura A: Suppressors of cytokine signaling and immunity. Nat Immunol 4: 1169–1176, 2003

    Google Scholar 

  7. Yu H, Jove R: The STATs of cancer–new molecular targets come of age. Nat Rev Cancer 4: 97–105, 2004

    Google Scholar 

  8. Catlett-Falcone R, et al.: Constitutive activation of STAT3 signaling confers resistance to apoptosis in human U266 myeloma cells. Immunity 10: 105–115, 1999

    Google Scholar 

  9. Grandis JR, et al.: Requirement of STAT3 but not Stat1 activation for epidermal growth factor receptor- mediated cell growth In vitro. J Clin Invest 102: 1385–1392, 1998

    Google Scholar 

  10. Bowman T, Garcia R, Turkson J, Jove R: STATs in oncogenesis. Oncogene 19: 2474–2488, 2000

    Google Scholar 

  11. Silvennoinen O, Schindler C, Schlessinger J, Levy DE: Ras-independent growth factor signaling by transcription factor tyrosine phosphorylation. Science 261: 1736–1739, 1993

    Google Scholar 

  12. Zhong Z, Wen Z, Darnell JE, Jr: STAT3: A STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6. Science 264: 95–98, 1994

    Google Scholar 

  13. Parsons JT, Parsons SJ: Src family protein tyrosine kinases: Cooperating with growth factor and adhesion signaling pathways. Curr Opin Cell Biol 9: 187–192, 1997

    Google Scholar 

  14. Danial NN, Rothman P: JAK-STAT signaling activated by Abl oncogenes. Oncogene 19: 2523–2531, 2000

    Google Scholar 

  15. Yoshikawa H et al.: SOCS-1, a negative regulator of the JAK/STAT pathway, is silenced by methylation in human hepatocellular carcinoma and shows growth-suppression activity. Nat Genet 28: 29–35, 2001

    Google Scholar 

  16. Galm O, Yoshikawa H, Esteller M, Osieka R, Herman JG: SOCS-1, a negative regulator of cytokine signaling, is frequently silenced by methylation in multiple myeloma. Blood 101: 2784–2788, 2003

    Google Scholar 

  17. Komazaki T et al.: Hypermethylation-associated inactivation of the SOCS-1 gene, a JAK/STAT inhibitor, in human pancreatic cancers. Jpn J Clin Oncol 34: 191–194, 2004

    Google Scholar 

  18. Nagai H et al.: Hypermethylation associated with inactivation of the SOCS-1 gene, a JAK/STAT inhibitor, in human hepatoblastomas. J Hum Genet 48: 65–69, 2003

    Google Scholar 

  19. He B et al.: SOCS-3 is frequently silenced by hypermethylation and suppresses cell growth in human lung cancer. Proc Natl Acad Sci USA 100: 14133–14138, 2003

    Google Scholar 

  20. Yu CL et al. Enhanced DNA-binding activity of a STAT3-related protein in cells transformed by the Src oncoprotein. Science 269: 81–83, 1995

    Google Scholar 

  21. Garcia R et al.: Constitutive activation of STAT3 in fibroblasts transformed by diverse oncoproteins and in breast carcinoma cells. Cell Growth Differ 8: 1267–1276, 1997

    Google Scholar 

  22. Bromberg JF, Horvath CM, Besser D, Lathem WW, Darnell JE, Jr: STAT3 activation is required for cellular transformation by v-src. Mol Cell Biol 18: 2553–2558, 1998

    Google Scholar 

  23. Turkson J et al.: STAT3 activation by Src induces specific gene regulation and is required for cell transformation. Mol Cell Biol 18: 2545–2552, 1998

    Google Scholar 

  24. Bromberg JF et al.: STAT3 as an oncogene. Cell 98: 295–303, 1999

    Google Scholar 

  25. Grandis JR et al.: Constitutive activation of STAT3 signaling abrogates apoptosis in squamous cell carcinogenesis in vivo. Proc Natl Acad Sci USA 97: 4227–4232, 2000

    Google Scholar 

  26. Buettner R, Mora LB, Jove R: Activated STAT signaling in human tumors provides novel molecular targets for therapeutic intervention. Clin Cancer Res 8: 945–954, 2002

    Google Scholar 

  27. Niu G et al.: Roles of activated Src and STAT3 signaling in melanoma tumor cell growth. Oncogene 21: 7001–7010, 2002

    Google Scholar 

  28. Karni R, Jove R, Levitzki A: Inhibition of pp60c-Src reduces Bcl-XL expression and reverses the transformed phenotype of cells overexpressing EGF and HER-2 receptors. Oncogene 18: 4654–4662, 1999

    Google Scholar 

  29. Megeney LA, Perry RL, LeCouter JE, Rudnicki MA: bFGF and LIF signaling activates STAT3 in proliferating myoblasts. Dev Genet 19: 139–145, 1996

    Google Scholar 

  30. Boney CM, Sekimoto H, Gruppuso PA, Frackelton AR, Jr.: Src family tyrosine kinases participate in insulin-like growth factor I mitogenic signaling in 3T3-L1 cells. Cell Growth Differ 12: 379–386, 2001

    Google Scholar 

  31. Boccaccio C et al.: Induction of epithelial tubules by growth factor HGF depends on the STAT pathway. Nature 391: 285–288, 1998

    Google Scholar 

  32. Easty DJ, Bennett DC: Protein tyrosine kinases in malignant melanoma. Melanoma Res 10: 401–411, 2000

    Google Scholar 

  33. Chin L: The genetics of malignant melanoma: Lessons from mouse and man. Nat Rev Cancer 3: 559–570, 2003

    Google Scholar 

  34. Yayon A, Ma YS, Safran M, Klagsbrun M, Halaban R: Suppression of autocrine cell proliferation and tumorigenesis of human melanoma cells and fibroblast growth factor transformed fibroblasts by a kinase-deficient FGF receptor 1: Evidence for the involvement of Src-family kinases. Oncogene 14: 2999–3009, 1997

    Google Scholar 

  35. Olayioye MA, Beuvink I, Horsch K, Daly JM, Hynes NE: ErbB receptor-induced activation of stat transcription factors is mediated by Src tyrosine kinases. J Biol Chem 274: 17209–17218, 1999

    Google Scholar 

  36. Song L, Turkson J, Karras JG, Jove R, Haura EB: Activation of STAT3 by receptor tyrosine kinases and cytokines regulates survival in human non-small cell carcinoma cells. Oncogene 22: 4150–4165, 2003

    Google Scholar 

  37. Zhang YW, Wang LM, Jove R, Vande Woude GF: Requirement of STAT3 signaling for HGF/SF-Met mediated tumorigenesis. Oncogene 21: 217–226, 2002

    Google Scholar 

  38. Natali PG et al.: Expression of the c-Met/HGF receptor in human melanocytic neoplasms: Demonstration of the relationship to malignant melanoma tumour progression. Br J Cancer 68: 746–750, 1993

    Google Scholar 

  39. Tomida M, Saito T: The human hepatocyte growth factor (HGF) gene is transcriptionally activated by leukemia inhibitory factor through the Stat binding element. Oncogene 23: 679–686, 2004

    Google Scholar 

  40. Potti A, Hille R, Koch M: Immunohistochemical determination of HER-2/neu in malignant melanoma. Anticancer Res 23: 4067–4069, 2003

    Google Scholar 

  41. Kluger HM et al.: Her2/neu is not a commonly expressed therapeutic target in melanoma—a large cohort tissue microarray study. Melanoma Res 14: 207–210, 2004

    Google Scholar 

  42. Stove C et al.: The heregulin/human epidermal growth factor receptor as a new growth factor system in melanoma with multiple ways of deregulation. J Invest Dermatol 121: 802–812, 2003

    Google Scholar 

  43. Kraehn GM, Schartl M, Peter RU: Human malignant melanoma. A genetic disease? Cancer 75: 1228–1237, 1995

    Google Scholar 

  44. Udart M, Utikal J, Krahn GM, Peter RU: Chromosome 7 aneusomy. A marker for metastatic melanoma? Expression of the epidermal growth factor receptor gene and chromosome 7 aneusomy in nevi, primary malignant melanomas and metastases. Neoplasia 3: 245–254, 2001

    Google Scholar 

  45. Wellbrock C et al.: Signalling by the oncogenic receptor tyrosine kinase Xmrk leads to activation of STAT5 in Xiphophorus melanoma. Oncogene 16: 3047–3056, 1998

    Google Scholar 

  46. Onishi M et al.: Identification and characterization of a constitutively active STAT5 mutant that promotes cell proliferation. Mol Cell Biol 18: 3871–3879, 1998

    Google Scholar 

  47. Yasuda Y et al.: Erythropoietin regulates tumour growth of human malignancies. Carcinogenesis 24: 1021–1029, 2003

    Google Scholar 

  48. Huang M et al.: Inhibition of Bcr-Abl kinase activity by PD180970 blocks constitutive activation of Stat5 and growth of CML cells. Oncogene 21: 8804–8816, 2002

    Google Scholar 

  49. Schwaller J et al.: Stat5 is essential for the myelo- and lymphoproliferative disease induced by TEL/JAK2. Mol Cell 6: 693–704, 2000

    Google Scholar 

  50. Levis M, Tse KF, Smith BD, Garrett E, Small D: A FLT3 tyrosine kinase inhibitor is selectively cytotoxic to acute myeloid leukemia blasts harboring FLT3 internal tandem duplication mutations. Blood 98: 885–887, 2001

    Google Scholar 

  51. Lou W, Ni Z, Dyer K, Tweardy DJ, Gao AC: Interleukin-6 induces prostate cancer cell growth accompanied by activation of stat3 signaling pathway. Prostate 42: 239–242, 2000

    Google Scholar 

  52. Swope VB, Abdel-Malek Z, Kassem LM, Nordlund JJ: Interleukins 1 alpha and 6 and tumor necrosis factor-alpha are paracrine inhibitors of human melanocyte proliferation and melanogenesis. J Invest Dermatol 96: 180–185, 1991

    Google Scholar 

  53. Lu C, Vickers MF, Kerbel RS: Interleukin 6: A fibroblast-derived growth inhibitor of human melanoma cells from early but not advanced stages of tumor progression. Proc Natl Acad Sci USA 89: 9215–9219, 1992

    Google Scholar 

  54. Lazar-Molnar E, Hegyesi H, Toth S, Falus A: Autocrine and paracrine regulation by cytokines and growth factors in melanoma. Cytokine 12: 547–554, 2000

    Google Scholar 

  55. Lu C et al.: Endogenous interleukin 6 can function as an in vivo growth- stimulatory factor for advanced-stage human melanoma cells. Clin Cancer Res 2: 1417–1425, 1996

    Google Scholar 

  56. Kortylewski M 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 18: 3742–3753, 1999

    Google Scholar 

  57. Levy DE, Lee CK: What does STAT3 do? J Clin Invest 109: 1143–1148, 2002

    Google Scholar 

  58. Kortylewski M et al.: Interferon-gamma-mediated growth regulation of melanoma cells: Involvement of STAT1-dependent and STAT1-independent signals. J Invest Dermatol 122: 414–422, 2004

    Google Scholar 

  59. Shankaran V et al.: IFNgamma and lymphocytes prevent primary tumour development and shape tumour immunogenicity. Nature 410: 1107–1111, 2001

    Google Scholar 

  60. Shen Y, Devgan G, Darnell JE, Jr. Bromberg JF: Constitutively activated STAT3 protects fibroblasts from serum withdrawal and UV-induced apoptosis and antagonizes the proapoptotic effects of activated Stat1. Proc Natl Acad Sci USA 98: 1543–1548, 2001

    Google Scholar 

  61. Costa-Pereira AP et al.: Mutational switch of an IL-6 response to an interferon-gamma-like response. Proc Natl Acad Sci USA 99: 8043–8047, 2002

    Google Scholar 

  62. Zhou P et al.: Mcl-1 in transgenic mice promotes survival in a spectrum of hematopoietic cell types and immortalization in the myeloid lineage. Blood 92: 3226–3239, 1998

    Google Scholar 

  63. Tang L et al.: Expression of apoptosis regulators in cutaneous malignant melanoma. Clin Cancer Res 4: 1865–1871, 1998

    Google Scholar 

  64. Leiter U, Schmid RM, Kaskel P, Peter RU, Krahn G: Antiapoptotic bcl-2 and bcl-xL in advanced malignant melanoma. Arch Dermatol Res 292: 225–232, 2000

    Google Scholar 

  65. Borner C et al.: Mutated N-ras upregulates Bcl-2 in human melanoma in vitro and in SCID mice. Melanoma Res 9: 347–350, 1999

    Google Scholar 

  66. Patel JH, Loboda AP, Showe MK, Showe LC, McMahon SB: Analysis of genomic targets reveals complex functions of MYC. Nat Rev Cancer 4: 562–568, 2004

    Google Scholar 

  67. Bardeesy N et al.: Dual inactivation of RB and p53 pathways in RAS-induced melanomas. Mol Cell Biol 21: 2144–2153, 2001

    Google Scholar 

  68. Shirogane T et al.: Synergistic roles for Pim-1 and c-Myc in STAT3-mediated cell cycle progression and antiapoptosis. Immunity 11: 709–719, 1999

    Google Scholar 

  69. Bowman T et al.: STAT3-mediated Myc expression is required for Src transformation and PDGF-induced mitogenesis. Proc Natl Acad Sci USA 98: 7319–7324, 2001

    Google Scholar 

  70. Kraehn GM et al.: Extra c-myc oncogene copies in high risk cutaneous malignant melanoma and melanoma metastases. Br J Cancer 84: 72–79, 2001

    Google Scholar 

  71. Chenevix-Trench G, Martin NG, Ellem KA: Gene expression in melanoma cell lines and cultured melanocytes: Correlation between levels of c-src-1, c-myc and p53. Oncogene 5: 1187–1193, 1990

    Google Scholar 

  72. Ross DA, Wilson GD: Expression of c-myc oncoprotein represents a new prognostic marker in cutaneous melanoma. Br J Surg 85: 46–51, 1998

    Google Scholar 

  73. Sinibaldi D et al.: Induction of p21WAF1/CIP1 and cyclin D1 expression by the Src oncoprotein in mouse fibroblasts: Role of activated STAT3 signaling. Oncogene 19: 5419–5427, 2000

    Google Scholar 

  74. Yoshida T et al.: Activation of STAT3 by the hepatitis C virus core protein leads to cellular transformation. J Exp Med 196: 641–653, 2002

    Google Scholar 

  75. Masuda M et al.: Constitutive activation of signal transducers and activators of transcription 3 correlates with cyclin D1 overexpression and may provide a novel prognostic marker in head and neck squamous cell carcinoma. Cancer Res 62: 3351–3355, 2002

    Google Scholar 

  76. Kijima T et al.: STAT3 activation abrogates growth factor dependence and contributes to head and neck squamous cell carcinoma tumor growth in vivo. Cell Growth Differ 13: 355–362, 2002

    Google Scholar 

  77. Vogelstein B, Lane D, Levine AJ: Surfing the p53 network. Nature 408: 307–310, 2000

    Google Scholar 

  78. Kamijo T et al.: Tumor suppression at the mouse INK4a locus mediated by the alternative reading frame product p19ARF. Cell 91: 649–659, 1997

    Google Scholar 

  79. Baker SJ et al.: Chromosome 17 deletions and p53 gene mutations in colorectal carcinomas. Science 244: 217–221, 1989

    Google Scholar 

  80. Baker SJ, Markowitz S, Fearon ER, Willson JK, Vogelstein B: Suppression of human colorectal carcinoma cell growth by wild-type p53. Science 249: 912–915, 1990

    Google Scholar 

  81. Baker SJ et al.: p53 gene mutations occur in combination with 17p allelic deletions as late events in colorectal tumorigenesis. Cancer Res 50: 7717–7722, 1990

    Google Scholar 

  82. Pharoah PD, Day NE, Caldas C: Somatic mutations in the p53 gene and prognosis in breast cancer: A meta-analysis. Br J Cancer 80: 1968–1973, 1999

    Google Scholar 

  83. Raman V et al.: Compromised HOXA5 function can limit p53 expression in human breast tumours. Nature 405: 974–978, 2000

    Google Scholar 

  84. Niu G et al.: Inhibition of p53 expression by STAT3 signaling. Submitted for publication

  85. Niu G et al.: Gene therapy with dominant-negative STAT3 suppresses growth of the murine melanoma B16 tumor in vivo. Cancer Res 59: 5059–5063, 1999

    Google Scholar 

  86. Niu G et al.: Overexpression of a dominant-negative signal transducer and activator of transcription 3 variant in tumor cells leads to production of soluble factors that induce apoptosis and cell cycle arrest. Cancer Res 61: 3276–3280, 2001

    Google Scholar 

  87. Thomas WD, Hersey P: TNF-related apoptosis-inducing ligand (TRAIL) induces apoptosis in Fas ligand-resistant melanoma cells and mediates CD4 T cell killing of target cells. J Immunol 161: 2195–2200, 1998

    Google Scholar 

  88. Folkman J: What is the evidence that tumors are angiogenesis dependent? J Natl Cancer Inst 82: 4–6, 1990

    Google Scholar 

  89. Millauer B, Shawver LK, Plate KH, Risau W, Ullrich A: Glioblastoma growth inhibited in vivo by a dominant-negative Flk-1 mutant. Nature 367: 576–579, 1994

    Google Scholar 

  90. Grunstein J, Roberts WG, Mathieu-Costello O, Hanahan D, Johnson RS: Tumor-derived expression of vascular endothelial growth factor is a critical factor in tumor expansion and vascular function. Cancer Res 59: 1592–1598, 1999

    Google Scholar 

  91. Niu G et al.: Constitutive STAT3 activity up-regulates VEGF expression and tumor angiogenesis. Oncogene 21: 2000–2008, 2002

    Google Scholar 

  92. Wei D et al.: STAT3 activation regulates the expression of vascular endothelial growth factor and human pancreatic cancer angiogenesis and metastasis. Oncogene 22: 319–329, 2003

    Google Scholar 

  93. Wei LH et al.: Interleukin-6 promotes cervical tumor growth by VEGF-dependent angiogenesis via a STAT3 pathway. Oncogene 22: 1517–1527, 2003

    Google Scholar 

  94. Xu Q et al.: STAT3 is a dual regulator of VEGF and an effective target for antiangiogenesis. Oncogene (in press) 2005

  95. Semenza GL: HIF-1 and mechanisms of hypoxia sensing. Curr Opin Cell Biol 13: 167–171, 2001

    Google Scholar 

  96. Semenza GL: Targeting HIF-1 for cancer therapy. Nat Rev Cancer 3: 721–732, 2003

    Google Scholar 

  97. Ravi R et al.: Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor 1alpha. Genes Dev 14: 34–44, 2000

    Google Scholar 

  98. Deo DD et al.: Phosphorylation of STAT-3 in response to basic fibroblast growth factor occurs through a mechanism involving platelet-activating factor, JAK-2, and Src in human umbilical vein endothelial cells. Evidence for a dual kinase mechanism. J Biol Chem 277: 21237–21245, 2002

    Google Scholar 

  99. Bartoli M et al.: VEGF differentially activates STAT3 in microvascular endothelial cells. Faseb J 17: 1562–1564 2003

    Google Scholar 

  100. Yahata Y et al.: Nuclear translocation of phosphorylated STAT3 is essential for vascular endothelial growth factor-induced human dermal microvascular endothelial cell migration and tube formation. J Biol Chem 278: 40026–40031, 2003

    Google Scholar 

  101. Bogenrieder T, Herlyn M: Axis of evil: Molecular mechanisms of cancer metastasis. Oncogene 22: 6524–6536, 2003

    Google Scholar 

  102. Denkins Y et al.: Brain metastases in melanoma: Roles of neurotrophins. Neuro-oncol 6: 154–165, 2004

    Google Scholar 

  103. Coussens LM, Werb Z: Matrix metalloproteinases and the development of cancer. Chem Biol 3: 895–904, 1996

    Google Scholar 

  104. Chambers AF, Matrisian LM: Changing views of the role of matrix metalloproteinases in metastasis. J Natl Cancer Inst 89: 1260–1270, 1997

    Google Scholar 

  105. Polette M, Birembaut P: Membrane-type metalloproteinases in tumor invasion. Int J Biochem Cell Biol 30: 1195–1202, 1998

    Google Scholar 

  106. Curran S, Murray GI: Matrix metalloproteinases in tumour invasion and metastasis. J Pathol 189: 300–308, 1999

    Google Scholar 

  107. Hendrix MJ, Seftor EA, Kirschmann DA, Quaranta V, Seftor RE: Remodeling of the microenvironment by aggressive melanoma tumor cells. Ann N Y Acad Sci 995: 151–161, 2003

    Google Scholar 

  108. Xie TX et al.: STAT3 activation regulates the expression of matrix metalloproteinase-2 and tumor invasion and metastasis. Oncogene 23: 3550–3560, 2004

    Google Scholar 

  109. Hanahan D, Weinberg RA: The hallmarks of cancer. Cell 100: 57–70, 2000

    Google Scholar 

  110. Dunn GP, Bruce AT, Ikeda H, Old LJ, Schreiber RD: Cancer immunoediting: From immunosurveillance to tumor escape. Nat Immunol 3: 991–998, 2002

    Google Scholar 

  111. Pardoll D: Does the immune system see tumors as foreign or self? Annu Rev Immunol 21: 807–839, 2003

    Google Scholar 

  112. Mocellin S, Wang E, Marincola FM: Cytokines and immune response in the tumor microenvironment. J Immunother 24: 392–407, 2001

    Google Scholar 

  113. Ohno S et al.: Tumor-associated macrophages: foe or accomplice of tumors? Anticancer Res 23: 4395–4409, 2003

    Google Scholar 

  114. Schwartsburd PM: Chronic inflammation as inductor of pro-cancer microenvironment: Pathogenesis of dysregulated feedback control. Cancer Metastasis Rev 22: 95–102, 2003

    Google Scholar 

  115. Prud’homme GJ: Altering immune tolerance therapeutically: The power of negative thinking. J Leukoc Biol 75: 586–599, 2004

    Google Scholar 

  116. Takeda K et al.: Enhanced Th1 activity and development of chronic enterocolitis in mice devoid of STAT3 in macrophages and neutrophils. Immunity 10: 39–49, 1999

    Google Scholar 

  117. Welte T et al.: STAT3 deletion during hematopoiesis causes Crohn’s disease-like pathogenesis and lethality: A critical role of STAT3 in innate immunity. Proc Natl Acad Sci USA 100: 1879–1884, 2003

    Google Scholar 

  118. Lee CK et al.: STAT3 is a negative regulator of granulopoiesis but is not required for G-CSF-dependent differentiation. Immunity 17: 63–72, 2002

    Google Scholar 

  119. Wang T et al.: Regulation of the innate and adaptive immune responses by Stat-3 signaling in tumor cells. Nat Med 10: 48–54, 2004

    Google Scholar 

  120. Hawiger D et al.: Dendritic cells induce peripheral T cell unresponsiveness under steady state conditions in vivo. J Exp Med 194: 769–779, 2001

    Google Scholar 

  121. Sotomayor EM et al.: Cross-presentation of tumor antigens by bone marrow-derived antigen-presenting cells is the dominant mechanism in the induction of T-cell tolerance during B-cell lymphoma progression. Blood 98: 1070–1077, 2001

    Google Scholar 

  122. Spiotto MT et al.: Increasing tumor antigen expression overcomes “ignorance” to solid tumors via crosspresentation by bone marrow-derived stromal cells. Immunity 17: 737–747, 2002

    Google Scholar 

  123. Liu K et al.: Immune tolerance after delivery of dying cells to dendritic cells in situ. J Exp Med 196: 1091–1097, 2002

    Google Scholar 

  124. Dhodapkar MV, Steinman RM: Antigen-bearing immature dendritic cells induce peptide-specific CD8(+) regulatory T cells in vivo in humans. Blood 100: 174–177, 2002

    Google Scholar 

  125. Steinman RM et al.: Dendritic cell function in vivo during the steady state: A role in peripheral tolerance. Ann N Y Acad Sci 987: 15–25, 2003

    Google Scholar 

  126. Vicari AP, Caux C, Trinchieri G: Tumour escape from immune surveillance through dendritic cell inactivation. Semin Cancer Biol 12: 33–42, 2002

    Google Scholar 

  127. Gabrilovich DI et al.: Production of vascular endothelial growth factor by human tumors inhibits the functional maturation of dendritic cells. Nat Med 2: 1096–1103, 1996

    Google Scholar 

  128. Steinbrink K, Wolfl M, Jonuleit H, Knop J, Enk AH, Induction of tolerance by IL-10-treated dendritic cells. J Immunol 159: 4772–4780, 1997

    Google Scholar 

  129. Menetrier-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 92: 4778–4791, 1998

    Google Scholar 

  130. Sombroek CC et al.: Prostanoids play a major role in the primary tumor-induced inhibition of dendritic cell differentiation. J Immunol 168: 4333–4343, 2002

    Google Scholar 

  131. Peguet-Navarro J et al.: Gangliosides from human melanoma tumors impair dendritic cell differentiation from monocytes and induce their apoptosis. J Immunol 170: 3488–3494, 2003

    Google Scholar 

  132. Corinti S, Albanesi C, la Sala A, Pastore S, Girolomoni G: Regulatory activity of autocrine IL-10 on dendritic cell functions. J Immunol 166: 4312–4318, 2001

    Google Scholar 

  133. Xie J, Wang Y, Freeman ME, 3rd Barlogie B, Yi Q: Beta 2-microglobulin as a negative regulator of the immune system: High concentrations of the protein inhibit in vitro generation of functional dendritic cells. Blood 101: 4005–4012, 2003

    Google Scholar 

  134. Nefedova Y et al.: Hyperactivation of STAT3 is involved in abnormal differentiation of dendritic cells in cancer. J Immunol 172: 464–474, 2004

    Google Scholar 

  135. Cheng F et al.: A critical role for STAT3 signaling in immune tolerance. Immunity 19: 425–436, 2003

    Google Scholar 

  136. Turkson J et al.: Phosphotyrosyl peptides block STAT3-mediated DNA binding activity, gene regulation, and cell transformation. J Biol Chem 276: 45443–45455, 2001

    Google Scholar 

  137. Turkson J et al.: Novel peptidomimetic inhibitors of signal transducer and activator of transcription 3 dimerization and biological activity. Mol Cancer Ther 3: 261–269, 2004

    Google Scholar 

  138. Turkson J et al.: Inhibition of constitutive STAT3 activation by novel platinum complexes with potent anti-tumor activity. Mol Cancer Ther 3: 1533–1542, 2004

    Google Scholar 

  139. Darnell JE, Jr.: Transcription factors as targets for cancer therapy. Nat Rev Cancer 2: 740–749, 2002

    Google Scholar 

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Kortylewski, M., Jove, R. & Yu, H. Targeting STAT3 affects melanoma on multiple fronts. Cancer Metastasis Rev 24, 315–327 (2005). https://doi.org/10.1007/s10555-005-1580-1

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