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


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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    ABSTRACT: Interleukin-6 (IL-6) encodes a cytokine protein, which causes inflammation, maintains immune homeostasis and plays an essential role in oral pathogenesis. The aim of this study was to evaluate the association between IL-6 (- 174 and - 572) G/C promoter gene polymorphisms and risk of OSCC among Indians. Single nucleotide polymorphism in IL-6 genes was genotyped in OSCC patients and healthy controls by PCR-RFLP method. Genotype and allele frequencies were analyzed by chi-square test and strength of associations by odds ratio with 95% confidence intervals. Frequency distribution of IL-6 (- 174) G/C gene polymorphism was significantly associated with OSCC patients in comparison to healthy controls (OR: 0.541, CI: 0.356-0.822; p: 0.004. However, frequency of IL-6 (- 572) G/C gene polymorphism was not significantly associated with OSCC patients (p > 0.05). The genotype GC and allele C of IL-6 (- 174) G/C gene polymorphism play a significant role in OSCC susceptibility.
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    • "Comparable mutations have not been well studied in breast cancer. However STAT1, STAT3, and STAT5 are often constitutively phosphorylated, seemingly due to elevated levels of cytokines and receptors.152 Preclinical studies showed that the interleukin-6/JAK2/STAT3 pathway is preferentially activated in basal-like breast cancer cells, and inhibition of JAK2 with NBP-BSK805 hinders the growth of patient-derived breast tumor xenografts.153 "
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    • "In several reports, an up-regulated IL-6/IL6R system has shown a prognostic impact in patients with hematologic malignancies and with solid tumors [20]. This background and the availability of novel IL-6 targeting moAbs [5] prompted us to investigate the possible influence of rs1800795 and rs8192284 on survival of patients with advanced gastric cancer. This information, beyond addressing a novel prognostic factor, may be relevant for the planning of clinical trials with anti-IL-6 therapies in this lethal disease. "
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    ABSTRACT: Background: IL-6 triggers oncogenic/angiogenic signals and the cytokine-dependent pro-cachexia cascade. The prognostic role of the functional IL-6 (promoter) rs1800795 and the IL-6R (receptor) rs8192284 single nucleotide polymorphisms (SNP) was studied in patients with advanced gastric cancer treated with palliative chemotherapy. Methods: One-hundred-sixty-one patients were genotyped for rs1800795 and rs8192284 SNPs using polymerase chain reaction based restriction fragment length polymorphism (PCR-RFLP) analysis assay. These results were studied for association with overall survival (OS). Results: In 161 assessable patients, frequencies of rs1800795 G/G, G/C and C/C genotypes were 46%, 42% and 12%, respectively. Frequencies of rs8192284 A/A, A/C and C/C genotypes were 36%, 45% and 19%, respectively. Carriers of the rs1800795 G/G and rs8192284 C/C genotypes showed the worst OS. In the multivariate model, rs1800795 G/G (1.69 hazard ratio; 95% confidence interval 1.18-2.42), and rs8192284 C/C (1.78 hazard ratio; 95% confidence interval 1.12-2.83) confirmed an adverse prognostic impact. Conclusions: In this population, genetic variants that up-regulate the IL-6 system showed impact on OS. This findings sustain the hypothesis that anti-IL-6 compounds deserve clinical studies as novel therapeutics in the palliative treatment of cancer patients.
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