Article

Targeting the interleukin-6/JAK/STAT pathway in human malignancies

Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College, New York, NY 10021, USA.
Journal of Clinical Oncology (Impact Factor: 18.43). 02/2012; 30(9):1005-14. DOI: 10.1200/JCO.2010.31.8907
Source: PubMed

ABSTRACT The Janus kinase/signal transducer and activator of transcription (Jak/Stat) pathway was discovered 20 years ago as a mediator of cytokine signaling. Since this time, more than 2,500 articles have been published demonstrating the importance of this pathway in virtually all malignancies. Although there are dozens of cytokines and cytokine receptors, four Jaks, and seven Stats, it seems that interleukin-6-mediated activation of Stat3 is a principal pathway implicated in promoting tumorigenesis. This transcription factor regulates the expression of numerous critical mediators of tumor formation and metastatic progression. This review will examine the relative importance and function of this pathway in nonmalignant conditions as well as malignancies (including tumor intrinsic and extrinsic), the influence of other Stats, the development of inhibitors to this pathway, and the potential role of inhibitors in controlling or eradicating cancers.

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    • "IL-6 may also have an essential role in the growth and differentiation of malignant tumors (Mandal et al., 2014; Zarogoulidis et al., 2013). IL-6 is a multifunctional cytokine of Th2 type which has both, pro-inflammatory and antiinflammatory cytokine activities (Sansone and Bromberg, 2012). It is a glycoprotein which consists of 184 amino acids and has a molecular weight of 26 kDa (Guo et al., 2012). "
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    • "STAT3 is activated downstream of several kinases including JAKs. While there is little evidence to date to support a critical function of JAKs in HNSCC, cumulative evidence implicates STAT3 activation in HNSCC progression [2] "
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    • "IL-6 Fibroblast and neutrophil recruitment Tumorigenesis, invasion, metastasis [124] [125] TNF-␣ Leucocyte infiltration Proliferation, invasion, angiogenesis [126] [127] Chemokines M-CSF (CSF-1) Macrophage recruitment Invasion, migration [128] [129] GM-CSF Neutrophil recruitment, keratinocyte proliferation Proliferation, differentiation [130] [131] MCP-1 (CCL2) Recruitment of monocytes and T cells Cancer growth and invasion [132] [133] IL-8 (CXCL8) Neutrophil recruitment, reepithelialization Angiogenesis, proliferation, migration [134] [135] GRO-␣ (CXCL1) Neutrophil recruitment, keratinocyte proliferation Invasion, tumorigenicity [136] [137] SDF-1 (CXCL12) Angiogenesis, lymphocyte recruitment Angiogenesis, metastasis [138] [139] [140] GRO-␤ (CXCL2, MIP2␣) Epithelial proliferation Recruitment of tumour-promoting leucocytes [141] [142] EGF, epidermal growth factor; TGF, transforming growth factor; BMP, bone morphogenic proteins; PDGF, platelet derived growth factor; VEGF, vascular endothelial growth factor; IGF, insulin like growth factor; EC, endothelial cells; CTGF; connective tissue growth factor; HGF, hepatocyte growth factor; SF, scatter factor; IL, interleukin; TNF, tumour necrosis factor; M-CSF, macrophage colony stimulating factor; GM-CSF, granulocyte monocyte colony stimulating factor; MCP, macrophage chemo-attractant protein; IP, interferon inducible protein; GRO, growth related oncogene; SDF, stromal derived factor; MIP, macrophage inflammatory protein. "
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