Interleukin-6 at the Host-Tumor Interface: STAT3 in Biomolecular Condensates in Cancer Cells

Abstract

It was recognized over 30 years ago that the polyfunctional cytokine interleukin-6 (IL-6) was an almost invariant presence at the host-tumor interface. The IL-6 in the tumor microenvironment was produced either by the cancer cell or by host stromal cells, or by tumor-infiltrating immune cells, or all of them. IL-6 effects in this context included local changes in tumor cell-cell and cell-substrate adhesion, enhanced motility, epithelial to mesenchymal transformation (EMT), and changes in cell proliferation rates in both solid tumors as well as hematologic dyscrasias. Locally produced IL-6 enhanced cancer-targeting functions of tumor-infiltrating macrophages and immune cells. Additionally, the sex-biased phenotype of certain cancers (e.g., hepatocellular carcinoma (HCC) which is 3-5-fold more common in men] was related to the inhibition of macrophage-derived IL-6 production by estradiol-17β (E2). In many circumstances, locally produced IL-6 reached the peripheral circulation and elicited systemic effects such as cachexia and paraneoplastic syndrome (including fever, increased erythrocyte sedimentation rate, increased levels of C-reactive protein in serum, hypoalbuminemia). This review highlights the EMT produced by IL-6 in cancer cells, as well as mechanisms underlying sex bias in HCC, enhanced IL-6 expression in cancer cells resulting from mutations in p53, consequent alterations in STAT3 transcriptional signaling, and the newer understanding of STAT3 nuclear bodies in the cancer cell as phase-separated biomolecular condensates and membraneless organelles (MLOs). Moreover, the perplexing issue of discrepant measurements of IL-6 in human circulation using different assays, especially in patients undergoing immunotherapy, is discussed. Additionally, the paradoxical chaperone (enhancing) effect of anti-IL-6 “neutralizing” antibodies on IL-6 in vivo and consequent limitations of immunotherapy using anti-IL-6 mAb is considered.

Lipid-Independent Regulation of PLIN5 via IL-6 through the JAK/STAT3 Axis in Hep3B Cells

“…One common mediator of IL-6 signaling is the signal transducer and activator of transcription 3 (STAT3) [ 25 , 26 ]. In our experiments, STAT3 phosphorylation was observed as early as 15 min after stimulation with IL-6, and persisted for up to 24 h ( Figure 4 ).…”

Variability, Expression, and Methylation of IL-6 and IL-8 Genes in Bladder Cancer Pathophysiology

“…In this case, the 7β-estradiol-bound estrogen receptor inhibits IKK activity and causes IκB protein degradation, blocking DNA binding by NF-κB. Consequently, this leads to a reduction in the intensity of the inflammatory response during the course of various diseases, including cancer [ 47 , 48 , 49 ]. Moreover, we also observed a significant increase in the expression of IL-6 in the case of the T1 stage compared to the Ta stage.…”

Plasma levels of interleukin‐6 mediate neurocognitive performance in older breast cancer survivors: The Thinking and Living With Cancer study

“…32,33 IL-6 is a unique pleiotropic cytokine, with proinflammatory and stimulatory activity on a wide variety of cell types, whose expression can be increased in cancer cells via p53 mutations, with resultant increased STAT3 transcriptional signaling. 34 IL-6 can be upregulated by tissue damage and/or be a secondary response to proinflammatory cytokines such as TNF-α, and is thought to contribute to chronic inflammatory activation via the production of C-reactive protein. 35 Research has also suggested that only very low circulating levels of IL-6 are needed to affect inflammatory cascades, 36 which may be one reason this immune marker had the strongest association in our study.…”