Crosstalk between cancer and immune cells: role of STAT3 in the tumour microenvironment (original) (raw)

• Hanahan, D. & Weinberg, R. A. The hallmarks of cancer. Cell 100, 57–70 (2000).
  Article CAS PubMed Google Scholar
• Bishop, J. M. Cancer: what should be done? Science 278, 995 (1997).
  Article CAS PubMed Google Scholar
• Vogelstein, B. & Kinzler, K. W. The multistep nature of cancer. Trends Genet. 9, 138–141 (1993).
  Article CAS PubMed Google Scholar
• Dunn, G. P., Bruce, A. T., Ikeda, H., Old, L. J. & Schreiber, R. D. Cancer immunoediting: from immunosurveillance to tumor escape. Nature Immunol. 3, 991–998 (2002). This is an insightful review on the mechanisms of immune surveillance and immune editing of tumours.
  Article CAS Google Scholar
• Pardoll, D. Does the immune system see tumors as foreign or self? Annu. Rev. Immunol. 21, 807–839 (2003).
  Article CAS PubMed Google Scholar
• Blattman, J. N. & Greenberg, P. D. Cancer immunotherapy: a treatment for the masses. Science 305, 200–205 (2004).
  Article CAS PubMed Google Scholar
• Gabrilovich, D. Mechanisms and functional significance of tumour-induced dendritic-cell defects. Nature Rev. Immunol. 4, 941–952 (2004).
  Article CAS Google Scholar
• Zou, W. Immunosuppressive networks in the tumour environment and their therapeutic relevance. Nature Rev. Cancer 5, 263–274 (2005).
  Article CAS Google Scholar
• Bissell, M. J. & Radisky, D. Putting tumours in context. Nature Rev. Cancer 1, 46–54 (2001).
  Article CAS Google Scholar
• Pollard, J. W. Tumour-educated macrophages promote tumour progression and metastasis. Nature Rev. Cancer 4, 71–78 (2004).
  Article CAS Google Scholar
• Yu, C. L. et al. Enhanced DNA-binding activity of a Stat3-related protein in cells transformed by the Src oncoprotein. Science 269, 81–83 (1995). This study provides the first evidence that STAT3 has a role in oncogenesis in that STAT3 is constitutively activated by SRC oncoprotein.
  Article CAS PubMed Google Scholar
• Bromberg, J. & Darnell, J. E. The role of STATs in transcriptional control and their impact on cellular function. Oncogene 19, 2468–2473 (2000).
  Article CAS PubMed Google Scholar
• Yu, H. & Jove, R. The STATs of cancer — new molecular targets come of age. Nature Rev. Cancer 4, 97–105 (2004). A comprehensive review on the role of STAT3 in cancer progression and on STAT3 as a target for cancer therapy.
  Article CAS Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed PubMed Central Google Scholar
• Wang, T. et al. Regulation of the innate and adaptive immune responses by Stat-3 signaling in tumor cells. Nature Med. 10, 48–54 (2004). This study provided the first evidence at the molecular level that oncogenesis, for which STAT3 is crucial, coordinates tumour immune evasion. STAT3 activity in tumour cells not only inhibits the expression of T H 1-type immune-stimulating molecules, it also promotes the expression of immunosuppressive factors, leading to the inhibition of DC maturation.
  Article PubMed CAS Google Scholar
• Kortylewski, M. et al. Inhibiting Stat3 signaling in the hematopoietic system elicits multicomponent antitumor immunity. Nature Med. 11, 1314–1321 (2005). This study shows that STAT3 is constitutively activated in diverse immune-cell subsets in the tumour microenvironment. STAT3 signalling allows tumour cells and local immune cells to resonate with one another, leading to immunosuppression.
  Article CAS PubMed Google Scholar
• Nabarro, S. et al. Coordinated oncogenic transformation and inhibition of host immune responses by the PAX3–FKHR fusion oncoprotein. J. Exp. Med. 202, 1399–1410 (2005). This paper shows that activation of STAT3 by an oncoprotein inhibits the host immune response in mouse models.
  Article CAS PubMed PubMed Central Google Scholar
• Sumimoto, H., Imabayashi, F., Iwata, T. & Kawakami, Y. The BRAF–MAPK signaling pathway is essential for cancer-immune evasion in human melanoma cells. J. Exp. Med. 203, 1651–1656 (2006). Results from this paper show that both STAT3 activation and the BRAF–MAPK signalling pathway can promote the expression of immunosuppressive factors such as IL-6, IL-10 and VEGF in human melanoma cells. Blocking either of these oncogenic signalling pathways in DCs decreases tumour-factor-induced inhibition of IL-12 expression.
  Article CAS PubMed PubMed Central Google Scholar
• Darnell, J. E., Kerr, I. M. & Stark, G. R. Jak–STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science 264, 1415–1421 (1994).
  Article CAS PubMed Google Scholar
• Taga, T. & Kishimoto, T. Gp130 and the interleukin-6 family of cytokines. Annu. Rev. Immunol. 15, 797–819 (1997).
  Article CAS PubMed Google Scholar
• Heinrich, P. C., Behrmann, I., Muller-Newen, G., Schaper, F. & Graeve, L. Interleukin-6-type cytokine signalling through the gp130/Jak/STAT pathway. Biochem. J. 334, 297–314 (1998).
  Article CAS PubMed PubMed Central Google Scholar
• Darnell, J. E. Studies of IFN-induced transcriptional activation uncover the Jak–Stat pathway. J. Interferon Cytokine Res. 18, 549–554 (1998).
  Article CAS PubMed Google Scholar
• Stark, G. R., Kerr, I. M., Williams, B. R., Silverman, R. H. & Schreiber, R. D. How cells respond to interferons. Annu. Rev. Biochem. 67, 227–264 (1998).
  Article CAS PubMed Google Scholar
• Heinrich, P. C. et al. Principles of interleukin (IL)-6-type cytokine signalling and its regulation. Biochem. J. 374, 1–20 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Wang, R., Cherukuri, P. & Luo, J. Activation of Stat3 sequence-specific DNA binding and transcription by p300/CREB-binding protein-mediated acetylation. J. Biol. Chem. 280, 11528–11534 (2005).
  Article CAS PubMed Google Scholar
• Yuan, Z. L., Guan, Y. J., Chatterjee, D. & Chin, Y. E. Stat3 dimerization regulated by reversible acetylation of a single lysine residue. Science 307, 269–273 (2005).
  Article CAS PubMed Google Scholar
• Silvennoinen, O., Schindler, C., Schlessinger, J. & Levy, D. E. Ras-independent growth factor signaling by transcription factor tyrosine phosphorylation. Science 261, 1736–1739 (1993).
  Article CAS PubMed Google Scholar
• Zhong, Z., Wen, Z. & Darnell, J. E. Stat3: a STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6. Science 264, 95–98 (1994).
  Article CAS PubMed Google Scholar
• Ruff-Jamison, S. et al. Epidermal growth factor and lipopolysaccharide activate Stat3 transcription factor in mouse liver. J. Biol. Chem. 269, 21933–21935 (1994).
  Article CAS PubMed Google Scholar
• Alexander, W. S. Suppressors of cytokine signalling (SOCS) in the immune system. Nature Rev. Immunol. 2, 410–416 (2002).
  Article CAS Google Scholar
• Kubo, M., Hanada, T. & Yoshimura, A. Suppressors of cytokine signaling and immunity. Nature Immunol. 4, 1169–1176 (2003).
  Article CAS Google Scholar
• Shuai, K. & Liu, B. Regulation of gene-activation pathways by PIAS proteins in the immune system. Nature Rev. Immunol. 5, 593–605 (2005).
  Article CAS Google Scholar
• 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).
  Article CAS PubMed PubMed Central Google Scholar
• Bromberg, J. F., Horvath, C. M., Besser, D., Lathem, W. W. & Darnell, J. E. Stat3 activation is required for cellular transformation by v-src. Mol. Cell. Biol. 18, 2553–2558 (1998).
  Article CAS PubMed PubMed Central Google Scholar
• Bromberg, J. F. et al. Stat3 as an oncogene. Cell 98, 295–303 (1999). Using a constitutively active mutant form of STAT3, this study formally establishes that STAT3 is an oncoprotein.
  Article CAS PubMed Google Scholar
• Catlett-Falcone, R. et al. Constitutive activation of Stat3 signaling confers resistance to apoptosis in human U266 myeloma cells. Immunity 10, 105–115 (1999).
  Article CAS PubMed Google Scholar
• Grandis, J. R. 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).
  Article CAS PubMed PubMed Central Google Scholar
• Coffer, P. J., Koenderman, L. & de Groot, R. P. The role of STATs in myeloid differentiation and leukemia. Oncogene 19, 2511–2522 (2000).
  Article CAS PubMed Google Scholar
• Lin, T. S., Mahajan, S. & Frank, D. A. STAT signaling in the pathogenesis and treatment of leukemias. Oncogene 19, 2496–2504 (2000).
  Article CAS PubMed Google Scholar
• Kortylewski, M., Jove, R. & Yu, H. Targeting STAT3 affects melanoma on multiple fronts. Cancer Metastasis Rev. 24, 315–327 (2005).
  Article CAS PubMed Google Scholar
• 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).
  CAS PubMed Google Scholar
• 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).
  CAS PubMed Google Scholar
• Niu, G. et al. Constitutive Stat3 activity up-regulates VEGF expression and tumor angiogenesis. Oncogene 21, 2000–2008 (2002).
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• Wei, L. H. et al. Interleukin-6 promotes cervical tumor growth by VEGF-dependent angiogenesis via a STAT3 pathway. Oncogene 22, 1517–1527 (2003).
  Article CAS PubMed Google Scholar
• Xu, Q. et al. Targeting Stat3 blocks both HIF-1 and VEGF expression induced by multiple oncogenic growth signaling pathways. Oncogene 24, 5552–5560 (2005).
  Article CAS PubMed Google Scholar
• Wojcik, E. J. et al. A novel activating function of c-Src and Stat3 on HGF transcription in mammary carcinoma cells. Oncogene 25, 2773–2784 (2006).
  Article CAS PubMed Google Scholar
• Xie, T. X. et al. Stat3 activation regulates the expression of matrix metalloproteinase-2 and tumor invasion and metastasis. Oncogene 23, 3550–3560 (2004).
  Article CAS PubMed Google Scholar
• Dechow, T. N. et al. Requirement of matrix metalloproteinase-9 for the transformation of human mammary epithelial cells by Stat3-C. Proc. Natl Acad. Sci. USA 101, 10602–10607 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Burdelya, L. et al. Stat3 activity in melanoma cells affects migration of immune effector cells and nitric oxide-mediated antitumor effects. J. Immunol. 174, 3925–3931 (2005).
  Article CAS PubMed Google Scholar
• Vicari, A. P., Caux, C. & Trinchieri, G. Tumour escape from immune surveillance through dendritic cell inactivation. Semin. Cancer Biol. 12, 33–42 (2002).
  Article CAS PubMed Google Scholar
• Steinman, R. M., Hawiger, D. & Nussenzweig, M. C. Tolerogenic dendritic cells. Annu. Rev. Immunol. 21, 685–711 (2003).
  Article CAS PubMed Google Scholar
• Nefedova, Y. et al. Hyperactivation of STAT3 is involved in abnormal differentiation of dendritic cells in cancer. J. Immunol. 172, 464–474 (2004).
  Article CAS PubMed Google Scholar
• Park, S. J. et al. IL-6 regulates in vivo dendritic cell differentiation through STAT3 activation. J. Immunol. 173, 3844–3854 (2004).
  Article CAS PubMed Google Scholar
• Kawakami, Y. et al. Regulation of dendritic cell maturation and function by Bruton's tyrosine kinase via IL-10 and Stat3. Proc. Natl Acad. Sci. USA 103, 153–158 (2006).
  Article CAS PubMed Google Scholar
• Cheng, F. et al. A critical role for Stat3 signaling in immune tolerance. Immunity 19, 425–436 (2003).
  Article CAS PubMed Google Scholar
• Sun, Z., Yao, Z., Liu, S., Tang, H. & Yan, X. An oligonucleotide decoy for Stat3 activates the immune response of macrophages to breast cancer. Immunobiology 211, 199–209 (2006).
  Article CAS PubMed Google Scholar
• Yu, P. et al. Intratumor depletion of CD4+ cells unmasks tumor immunogenicity leading to the rejection of late-stage tumors. J. Exp. Med. 201, 779–791 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Nishikawa, H. et al. IFN-γ controls the generation/activation of CD4+ CD25+ regulatory T cells in antitumor immune response. J. Immunol. 175, 4433–4440 (2005).
  Article CAS PubMed Google Scholar
• Larmonier, N. et al. Tumor-derived CD4+CD25+ regulatory T cell suppression of dendritic cell function involves TGF-β and IL-10. Cancer Immunol. Immunother. 56, 48–59 (2007).
  Article CAS PubMed Google Scholar
• Liyanage, U. K. et al. Prevalence of regulatory T cells is increased in peripheral blood and tumor microenvironment of patients with pancreas or breast adenocarcinoma. J. Immunol. 169, 2756–2761 (2002).
  Article CAS PubMed Google Scholar
• Woo, E. Y. et al. Regulatory CD4+CD25+ T cells in tumors from patients with early-stage non-small cell lung cancer and late-stage ovarian cancer. Cancer Res. 61, 4766–4772 (2001).
  CAS PubMed Google Scholar
• Zou, W. Regulatory T cells, tumour immunity and immunotherapy. Nature Rev. Immunol. 6, 295–307 (2006).
  Article CAS Google Scholar
• Curiel, T. J. et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nature Med. 10, 942–949 (2004).
  Article CAS PubMed Google Scholar
• Wei, S. et al. Plasmacytoid dendritic cells induce CD8+ regulatory T cells in human ovarian carcinoma. Cancer Res. 65, 5020–5026 (2005).
  Article CAS PubMed Google Scholar
• Sakaguchi, S. Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and non-self. Nature Immunol. 6, 345–352 (2005).
  Article CAS Google Scholar
• Shevach, E. M. CD4+ CD25+ suppressor T cells: more questions than answers. Nature Rev. Immunol. 2, 389–400 (2002).
  Article CAS Google Scholar
• Chen, W. et al. Conversion of peripheral CD4+CD25− naive T cells to CD4+CD25+ regulatory T cells by TGF-β induction of transcription factor Foxp3. J. Exp. Med. 198, 1875–1886 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Fantini, M. C. et al. Cutting edge: TGF-β induces a regulatory phenotype in CD4+CD25− T cells through Foxp3 induction and down-regulation of Smad7. J. Immunol. 172, 5149–5153 (2004).
  Article CAS PubMed Google Scholar
• Kinjyo, I. et al. Loss of SOCS3 in T helper cells resulted in reduced immune responses and hyperproduction of interleukin 10 and transforming growth factor-β1. J. Exp. Med. 203, 1021–1031 (2006). This study shows that increased STAT3 signalling, as a result of Socs3 ablation, is crucial for the expression of IL-10 and TGF-β by T H cells, indicating a crucial role for STAT3 in T Reg cells.
  Article CAS PubMed PubMed Central Google Scholar
• Kasprzycka, M., Marzec, M., Liu, X., Zhang, Q. & Wasik, M. A. Nucleophosmin/anaplastic lymphoma kinase (NPM/ALK) oncoprotein induces the T regulatory cell phenotype by activating STAT3. Proc. Natl Acad. Sci. USA 103, 9964–9969 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Doganci, A. et al. The IL-6Rα chain controls lung CD4+CD25+ TR eg development and function during allergic airway inflammation in vivo. J. Clin. Invest. 115, 313–325 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Zorn, E. et al. IL-2 regulates FOXP3 expression in human CD4+CD25+ regulatory T cells through a STAT-dependent mechanism and induces the expansion of these cells in vivo. Blood 108, 1571–1579 (2006). This paper shows that IL-2-induced FOXP3 expression in human T Reg cells is mediated by STAT3 and STAT5.
  Article CAS PubMed PubMed Central Google Scholar
• Antov, A., Yang, L., Vig, M., Baltimore, D. & Van Parijs, L. Essential role for STAT5 signaling in CD25+CD4+ regulatory T cell homeostasis and the maintenance of self-tolerance. J. Immunol. 171, 3435–3441 (2003).
  Article CAS PubMed Google Scholar
• Snow, J. W. et al. Loss of tolerance and autoimmunity affecting multiple organs in STAT5A/5B-deficient mice. J. Immunol. 171, 5042–5050 (2003).
  Article CAS PubMed Google Scholar
• Chan, S. M., Ermann, J., Su, L., Fathman, C. G. & Utz, P. J. Protein microarrays for multiplex analysis of signal transduction pathways. Nature Med. 10, 1390–1396 (2004).
  Article CAS PubMed Google Scholar
• Anderson, P. O. et al. IL-2 overcomes the unresponsiveness but fails to reverse the regulatory function of antigen-induced T regulatory cells. J. Immunol. 174, 310–319 (2005).
  Article CAS PubMed Google Scholar
• Dercamp, C., Chemin, K., Caux, C., Trinchieri, G. & Vicari, A. P. Distinct and overlapping roles of interleukin-10 and CD25+ regulatory T cells in the inhibition of antitumor CD8 T-cell responses. Cancer Res. 65, 8479–8486 (2005).
  Article CAS PubMed Google Scholar
• Langowski, J. L. et al. IL-23 promotes tumour incidence and growth. Nature 442, 461–465 (2006).
  Article CAS PubMed Google Scholar
• Hoentjen, F., Sartor, R. B., Ozaki, M. & Jobin, C. STAT3 regulates NF-κB recruitment to the IL-12p40 promoter in dendritic cells. Blood 105, 689–696 (2005).
  Article CAS PubMed Google Scholar
• Chen, Z. et al. Selective regulatory function of Socs3 in the formation of IL-17-secreting T cells. Proc. Natl Acad. Sci. USA 103, 8137–8142 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Karin, M. & Greten, F. R. NF-κB: linking inflammation and immunity to cancer development and progression. Nature Rev. Immunol. 5, 749–759 (2005).
  Article CAS Google Scholar
• Dalwadi, H. et al. Cyclooxygenase-2-dependent activation of signal transducer and activator of transcription 3 by interleukin-6 in non-small cell lung cancer. Clin. Cancer Res. 11, 7674–7682 (2005).
  Article CAS PubMed Google Scholar
• Shankaran, V. et al. IFNγ and lymphocytes prevent primary tumour development and shape tumour immunogenicity. Nature 410, 1107–1111 (2001).
  Article CAS PubMed Google Scholar
• Alonzi, T. et al. Induced somatic inactivation of STAT3 in mice triggers the development of a fulminant form of enterocolitis. Cytokine 26, 45–56 (2004).
  Article CAS PubMed Google Scholar
• Turkson, J. et al. Phosphotyrosyl peptides block Stat3-mediated DNA binding activity, gene regulation, and cell transformation. J. Biol. Chem. 276, 45443–45455 (2001).
  Article CAS PubMed Google Scholar
• Turkson, J. et al. A novel platinum compound inhibits constitutive Stat3 signaling and induces cell cycle arrest and apoptosis of malignant cells. J. Biol. Chem. 280, 32979–32988 (2005).
  Article CAS PubMed Google Scholar
• Turkson, J. et al. Inhibition of constitutive signal transducer and activator of transcription 3 activation by novel platinum complexes with potent antitumor activity. Mol. Cancer Ther. 3, 1533–1542 (2004).
  CAS PubMed Google Scholar
• van Elsas, A., Hurwitz, A. A. & Allison, J. P. Combination immunotherapy of B16 melanoma using anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and granulocyte/macrophage colony-stimulating factor (GM-CSF)-producing vaccines induces rejection of subcutaneous and metastatic tumors accompanied by autoimmune depigmentation. J. Exp. Med. 190, 355–366 (1999).
  Article CAS PubMed PubMed Central Google Scholar
• Riley, J. L. & June, C. H. The CD28 family: a T-cell rheostat for therapeutic control of T-cell activation. Blood 105, 13–21 (2005).
  Article CAS PubMed Google Scholar
• Shen, L., Evel-Kabler, K., Strube, R. & Chen, S. Y. Silencing of SOCS1 enhances antigen presentation by dendritic cells and antigen-specific anti-tumor immunity. Nature Biotechnol. 22, 1546–1553 (2004).
  Article CAS Google Scholar
• Kryczek, I. et al. B7-H4 expression identifies a novel suppressive macrophage population in human ovarian carcinoma. J. Exp. Med. 203, 871–881 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Mellor, A. L. & Munn, D. H. IDO expression by dendritic cells: tolerance and tryptophan catabolism. Nature Rev. Immunol. 4, 762–774 (2004).
  Article CAS Google Scholar
• Rosenberg, S. A., Yang, J. C. & Restifo, N. P. Cancer immunotherapy: moving beyond current vaccines. Nature Med. 10, 909–915 (2004).
  Article CAS PubMed Google Scholar
• Pardoll, D. M. Spinning molecular immunology into successful immunotherapy. Nature Rev. Immunol. 2, 227–238 (2002).
  Article CAS Google Scholar
• Steinman, R. M. & Mellman, I. Immunotherapy: bewitched, bothered, and bewildered no more. Science 305, 197–200 (2004).
  Article CAS PubMed Google Scholar
• Vicari, A. P. et al. Reversal of tumor-induced dendritic cell paralysis by CpG immunostimulatory oligonucleotide and anti-interleukin 10 receptor antibody. J. Exp. Med. 196, 541–549 (2002).
  Article CAS PubMed PubMed Central Google Scholar
• Nefedova, Y. et al. Regulation of dendritic cell differentiation and antitumor immune response in cancer by pharmacologic-selective inhibition of the janus-activated kinase 2/signal transducers and activators of transcription 3 pathway. Cancer Res. 65, 9525–9535 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Kitamura, H. et al. IL-6–STAT3 controls intracellular MHC class II αβ dimer level through cathepsin S activity in dendritic cells. Immunity 23, 491–502 (2005).
  Article CAS PubMed Google Scholar
• Kammertoens, T., Schuler, T. & Blankenstein, T. Immunotherapy: target the stroma to hit the tumor. Trends Mol. Med. 11, 225–231 (2005).
  Article CAS PubMed Google Scholar
• Wang, S. et al. Tumor evasion of the immune system: inhibiting p38 MAPK signaling restores the function of dendritic cells in multiple myeloma. Blood 107, 2432–2439 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Dauer, D. J. et al. Stat3 regulates genes common to both wound healing and cancer. Oncogene 24, 3397–3408 (2005).
  Article CAS PubMed Google Scholar
• Sano, S. et al. Keratinocyte-specific ablation of Stat3 exhibits impaired skin remodeling, but does not affect skin morphogenesis. EMBO J. 18, 4657–4668 (1999).
  Article CAS PubMed PubMed Central Google Scholar
• Chiarle, R. et al. Stat3 is required for ALK-mediated lymphomagenesis and provides a possible therapeutic target. Nature Med. 11, 623–629 (2005).
  Article CAS PubMed Google Scholar
• Okada, S. et al. Conditional ablation of Stat3 or Socs3 discloses a dual role for reactive astrocytes after spinal cord injury. Nature Med. 12, 829–834 (2006).
  Article CAS PubMed Google Scholar
• Odajima, J. et al. Full oncogenic activities of v-Src are mediated by multiple signaling pathways. Ras as an essential mediator for cell survival. J. Biol. Chem. 275, 24096–24105 (2000).
  Article CAS PubMed Google Scholar
• Ning, Z. Q., Li, J., McGuinness, M. & Arceci, R. J. STAT3 activation is required for Asp816 mutant c-Kit induced tumorigenicity. Oncogene 20, 4528–4536 (2001).
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed PubMed Central Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• Epling-Burnette, P. K. et al. Inhibition of STAT3 signaling leads to apoptosis of leukemic large granular lymphocytes and decreased Mcl-1 expression. J. Clin. Invest. 107, 351–362 (2001).
  Article CAS PubMed PubMed Central Google Scholar
• Niu, G. et al. Roles of activated Src and Stat3 signaling in melanoma tumor cell growth. Oncogene 21, 7001–7010 (2002).
  Article CAS PubMed Google Scholar
• Aoki, Y., Feldman, G. M. & Tosato, G. Inhibition of STAT3 signaling induces apoptosis and decreases survivin expression in primary effusion lymphoma. Blood 101, 1535–1542 (2003).
  Article CAS PubMed Google Scholar
• Amin, H. M. et al. Selective inhibition of STAT3 induces apoptosis and G1 cell cycle arrest in ALK-positive anaplastic large cell lymphoma. Oncogene 23, 5426–5434 (2004).
  Article CAS PubMed Google Scholar
• Gritsko, T. et al. Persistent activation of stat3 signaling induces survivin gene expression and confers resistance to apoptosis in human breast cancer cells. Clin. Cancer Res. 12, 11–19 (2006).
  Article CAS PubMed Google Scholar
• Niu, G. et al. Role of Stat3 in regulating p53 expression and function. Mol. Cell. Biol. 25, 7432–7440 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Hung, W. & Elliott, B. Co-operative effect of c-Src tyrosine kinase and Stat3 in activation of hepatocyte growth factor expression in mammary carcinoma cells. J. Biol. Chem. 276, 12395–12403 (2001).
  Article CAS PubMed Google Scholar
• Xie, T. X. et al. Activation of stat3 in human melanoma promotes brain metastasis. Cancer Res. 66, 3188–3196 (2006).
  Article CAS PubMed Google Scholar
• Jung, J. E. et al. STAT3 is a potential modulator of HIF-1-mediated VEGF expression in human renal carcinoma cells. FASEB J. 19, 1296–1298 (2005).
  Article CAS PubMed Google Scholar
• Herbeuval, J. P., Lelievre, E., Lambert, C., Dy, M. & Genin, C. Recruitment of STAT3 for production of IL-10 by colon carcinoma cells induced by macrophage-derived IL-6. J. Immunol. 172, 4630–4636 (2004).
  Article CAS PubMed Google Scholar