Targeting the interleukin-6/Jak/stat pathway in human malignancies

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.

Fig 1.

Heterogeneity in phosphorylated signal transducer and activator of transcription 3 (pStat3) expression. (A) Immunohistochemical analysis of pStat3 levels in a primary invasive ductal carcinoma. Nuclear pStat3 is detected in stromal (blue arrow) and endothelial cells (red arrow) and with variable levels in tumor cells (black arrow, strong staining; gray arrow, weak staining). (B) Schematic demonstrating this variability in pStat3 expression.

Fig 2.

Signal transducer and activator of transcription 3 (Stat3) signaling. Canonical: Stat3 is tyrosine phosphorylated by Janus kinase (Jak) kinases in response to cytokine/growth factor activation of cell surface receptors (eg, receptor tyrosine kinases [RTKs], glycoprotein 130 [gp130] with either interleukin-6 receptor [IL-6R] or soluble IL-6R [sIL-6R]). On tyrosine phosphorylation (PY), Stat3 dimerizes and localizes to the nucleus, where it binds to Stat3 responsive elements. Stat3 is also serine phosphorylated (PS). Soluble factors that activate Stat3 include the IL-6 family of cytokines. Noncanonical: Unphosphorylated Stat3 can bind to either nuclear factor κB (NFκB) or CD44 in the cytoplasm; the complexes translocate into the nucleus, where they bind NFκB (IKE) and Stat3 DNA-binding elements. Acetylated Stat3 is required for association with CD44. PS Stat3 and PY Stat3 can also localize into the mitochondria, where they modulate ATP production. Agents to inhibit the Stat3 canonical pathway include targeting Jak (CEP-701, XL019, INCB018424, AZD1480) and the IL-6/sIL-6R interaction (tocilizumab, CNTO-328). HAT, histone acetyltransferase; HDAC, histone deacetylase; ISRE, interferon stimulated response element; MAPK, mitogen-activated protein kinase; mTOR, mammalian target of rapamycin; PIAS, protein inhibitors of activated Stat; SOCS, suppressor of cytokin signaling.