The Role of the IL-6 Cytokine Family in Epithelial-Mesenchymal Plasticity in Cancer Progression

Abstract

Epithelial-mesenchymal plasticity (EMP) plays critical roles during embryonic development, wound repair, fibrosis, inflammation and cancer. During cancer progression, EMP results in heterogeneous and dynamic populations of cells with mixed epithelial and mesenchymal characteristics, which are required for local invasion and metastatic dissemination. Cancer development is associated with an inflammatory microenvironment characterized by the accumulation of multiple immune cells and pro-inflammatory mediators, such as cytokines and chemokines. Cytokines from the interleukin 6 (IL-6) family play fundamental roles in mediating tumour-promoting inflammation within the tumour microenvironment, and have been associated with chronic inflammation, autoimmunity, infectious diseases and cancer, where some members often act as diagnostic or prognostic biomarkers. All IL-6 family members signal through the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway and are able to activate a wide array of signalling pathways and transcription factors. In general, IL-6 cytokines activate EMP processes, fostering the acquisition of mesenchymal features in cancer cells. However, this effect may be highly context dependent. This review will summarise all the relevant literature related to all members of the IL-6 family and EMP, although it is mainly focused on IL-6 and oncostatin M (OSM), the family members that have been more extensively studied.

Keywords: IL-6; cancer; cytokines; epithelial–mesenchymal plasticity; epithelial–mesenchymal transition; invasion; migration; oncostatin M (OSM).

Figure 1

Schematic representation of the effects of interleukin 6 (IL-6) and oncostatin M (OSM) in epithelial–mesenchymal plasticity (EMP) and the downstream pathways and mediators involved. Black and red colours indicate pro and anti-EMP functions, respectively. T arrows indicate inhibition. Dashed arrows indicate EMP promotion by EMT-TF protein stabilisation. EMT-TFs: Transcription factors involved in EMP.

Figure 2

Schematic representation of the different effects of interleukin 11 (IL-11), leukaemia inhibitory factor (LIF) and interleukin 27 (IL-27) in epithelial–mesenchymal plasticity (EMP) and the downstream pathways and mediators involved. Black and red colours indicate pro- and anti-EMP functions, respectively. T arrows indicate inhibition. Dashed arrows indicate EMP promotion by EMT-TF protein stabilization. EMT-TFs: Transcription factors involved in EMP.