Figure 4.

Stat3 links inflammation to cancer. Inflammation and cancer are functionally linked by intrinsic, Stat3-dependent autocrine feedback loops in neoplastic epithelium (red arrows) and extrinsic, feedforward and often reciprocal interactions between tumour, inflammatory and stromal cells that collectively make up the microenvironment (green arrows) [167]. The ubiquitous expression of gp130 and the capacity of STAT3 to stimulate its own transcription as well as that of gp130 ligands (in particular IL6 and IL11) also provides numerous amplification loops between the different cell types. Furthermore, limited responsiveness to IL6 and IL11 imposed by restricted expression of the ligand-specific receptor α-subunits can be overcome by IL6-transsignaling [90]. Excessive cell-intrinsic STAT3 activation is also triggered by oncogenic events from (epi-)genetic activation of positive regulators (i.e. receptor (-associated) TKs) and loss of function mutations of negative regulators (i.e. SOCS3). Expression of IL6 is also directly induced by NF-κB and indirectly through a feedback mechanism including lin28 and the let7-microRNA, while latent Stat3 in conjunction with NF-κB triggers non-canonical IL6 expression. Epithelial NF-κB and STAT3 are activated in response to the abundantly present inflammatory cytokines IL1, TNFα and IL6 which are released from TLR-activated myeloid cell (macrophages), with IL6 and IL11 also contributed by tumour-associated stromal fibroblast and myoepithelial cells. Meanwhile, release of IL17 and IL22 from mature Th17 cells provide an additional extrinsic link which results in excessive STAT3 activation in tumour cells.