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.

Cyclophilin D Extramitochondrial Signaling Controls Cell Cycle Progression and Chemokine-directed Cell Motility*

“…S1) (24). Consistent with these predictions, CypD knockdown in LN229 cells or deletion of CypD in MEFs resulted in increased STAT3 luciferase promoter activity compared with control cultures (Fig.…”

“…5G) or CypD-silenced LN229 transfectants (data not shown). In control experiments, treatment of CypD Ϫ/Ϫ MEFs with Dasatinib, a small molecule inhibitor of the Src kinase that also activates STAT3 (24), abrogated Src phosphorylation on Tyr-416 but had no effect on Tyr-705 phosphorylation of STAT3 (Fig. 5H).…”

Synergistic cross‐talk of hedgehog and interleukin‐6 signaling drives growth of basal cell carcinoma

“…Small‐molecule inhibitors or antagonistic antibodies targeting critical effectors of IL6 signaling including IL6 itself, IL6R, gp130, JAK1/JAK2 and STAT3 have recently been approved or are currently evaluated in several clinical trials with patients suffering from cancer entities with a documented involvement of HH/GLI signaling such as breast and non‐small‐cell lung cancer (for review, see Refs. 17, 21, 50 and references therein).…”

“…This so‐called IL6 trans‐signaling allows IL6 to target cells not expressing the membrane‐bound IL6R 20. The therapeutic relevance of IL6 signaling in malignant development is currently evaluated in a number of clinical trials with antibodies and small‐molecule inhibitors targeting oncogenic IL6/STAT3 signaling 17, 21…”

TNFα promotes osteosarcoma progression by maintaining tumor cells in an undifferentiated state

“…osteosarcoma patients, 9 and IL-6 is implicated in the development of various tumors. [15][16][17] Thus, we transplanted AX cells into IL-6-deficient or wild-type mice in order to compare mouse survival rates (Figure 1b). However, survival rates of AX cell-bearing mice of either genotype were comparable (Figure 1b), suggesting that IL-6 does not function in AX cell tumorigenesis in vivo.…”