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.

Mesenchymal-epithelial transition in lymph node metastases of oral squamous cell carcinoma is accompanied by ZEB1 expression

“…CAF3 fibroblasts showed pronounced gene expression of alpha smooth muscle actin ( ACTA2 ), which characterizes myofibroblasts, and also Interleukin 6 ( IL-6 ) [34]. IL-6 does not only exert immune-regulatory functions but is also able to promote EMP processes [34, 35]. Interestingly, CAF3 clusters closely to myoblast-like cells, which while lacking expression of fibroblast markers such as collagens or FN1 , express typical markers for myogenic differentiation such as MYF5 and MYF6 [36] (Figure 5B, C, Supplementary Figure 7A).…”

TNF-α Indicates Radiation-induced Liver Injury After Interstitial High Dose-rate Brachytherapy

“…Yet, iBT induced a significant decrease in our cohort. It is known that cytokines from the IL-6 family play fundamental roles in mediating tumor-promoting inflammation within the tumor microenvironment and cancer progression (23,38). Thus, it is currently under discussion of how the immunobiology of IL-6 may influence the clinical decisions, and more specifically, how and when an inhibition of this cytokine might improve disease outcome and patient wellbeing.…”

Hyaluronan Functions in Wound Repair That Are Captured to Fuel Breast Cancer Progression

“…However, IL–6 also plays a key modulatory role in the switch from a pro–inflammatory to immunosuppressive microenvironment required for wound resolution [ 54 ]. The increased expression of IL–6 is also linked to breast cancer progression [ 48 ], where it performs both immunomodulatory functions similar to those in wound repair [ 55 ]. This cytokine has also been shown to modulate tumor cell plasticity, which impacts breast cancer progression and chemo–resistance [ 55 ].…”

“…The increased expression of IL–6 is also linked to breast cancer progression [ 48 ], where it performs both immunomodulatory functions similar to those in wound repair [ 55 ]. This cytokine has also been shown to modulate tumor cell plasticity, which impacts breast cancer progression and chemo–resistance [ 55 ]. Therefore, deeper analyses of the links between CEMIP and IL–6 are potentially important for understanding the commonalities between wound repair and cancer metastasis, as well as providing potential therapeutic targets to control both of these processes.…”