IL-6 Mediates Cross-Talk between Tumor Cells and Activated Fibroblasts in the Tumor Microenvironment

Abstract

The tumor microenvironment (TME) plays a major role in the pathogenesis of multiple cancer types, including upper-gastrointestinal (GI) cancers that currently lack effective therapeutic options. Cancer-associated fibroblasts (CAF) are an essential component of the TME, contributing to tumorigenesis by secreting growth factors, modifying the extracellular matrix, supporting angiogenesis, and suppressing antitumor immune responses. Through an unbiased approach, we have established that IL-6 mediates cross-talk between tumor cells and CAF not only by supporting tumor cell growth, but also by promoting fibroblast activation. As a result, IL-6 receptor (IL6Rα) and downstream effectors offer opportunities for targeted therapy in upper-GI cancers. IL-6 loss suppressed tumorigenesis in physiologically relevant three-dimensional (3D) organotypic and 3D tumoroid models and murine models of esophageal cancer. Tocilizumab, an anti-IL6Rα antibody, suppressed tumor growth in part via inhibition of STAT3 and MEK/ERK signaling. Analysis of a pan-cancer TCGA dataset revealed an inverse correlation between IL-6 and IL6Rα overexpression and patient survival. Therefore, we expanded evaluation of tocilizumab to head and neck squamous cell carcinoma patient-derived xenografts and gastric adenocarcinoma xenografts, demonstrating suppression of tumor growth and altered STAT3 and ERK1/2 gene signatures. We used small-molecule inhibitors of STAT3 and MEK1/2 signaling to suppress tumorigenesis in the 3D organotypic model of esophageal cancer. We demonstrate that IL6 is a major contributor to the dynamic cross-talk between tumor cells and CAF in the TME. Our findings provide a translational rationale for inhibition of IL6Rα and downstream signaling pathways as a novel targeted therapy in oral-upper-GI cancers. These findings demonstrate the interaction of esophageal cancer and cancer-associated fibroblasts through IL-6 signaling, providing rationale for a novel therapeutic approach to target these cancers. .

Circular RNA hsa_circ_0000654 promotes esophageal squamous cell carcinoma progression by regulating the miR‐149‐5p/IL‐6/STAT3 pathway

“…IL‐6 acts directly on tumor cells and induces the expression of STAT3 target genes, which then encode proteins that drive tumor cell proliferation and/or survival . The IL‐6/STAT3 signaling pathway is abnormally activated in diverse tumors, such as nasopharyngeal carcinoma, breast cancer, and ESCC . Comparatively, the mechanism that causes abnormal activation of IL‐6/STAT3 in ESCC needs further investigation.…”

“…24 The IL-6/STAT3 signaling pathway is abnormally activated in diverse tumors, such as nasopharyngeal carcinoma, breast cancer, and ESCC. [25][26][27] Comparatively, the mechanism that causes abnormal activation of IL-6/STAT3 in ESCC needs further investigation.…”

Non‐lethal proteasome inhibition activates pro‐tumorigenic pathways in multiple myeloma cells

“…IL6 levels predict event‐free survival in paediatric AML suggesting a mechanism of chemotherapy resistance and IL32α promotes the proliferation of MM cells by inducing production of IL6 in bone marrow stromal cells . Consistently, glioblastoma‐derived IL6 induces immunosuppressive peripheral myeloid cell PD‐L1 and promotes tumour growth; also, in the tumour microenvironment of upper‐gastrointestinal cancers, IL6 mediates the cross‐talk between tumour cells and pro‐tumorigenic activated fibroblasts . Similarly, IL8 is implicated in cancer cell growth, survival, angiogenesis and metastasis in several tumours .…”

“…54 Consistently, glioblastoma-derived IL6 induces immunosuppressive peripheral myeloid cell PD-L1 and promotes tumour growth 55 ; also, in the tumour microenvironment of upper-gastrointestinal cancers, IL6 mediates the cross-talk between tumour cells and pro-tumorigenic activated fibroblasts. 56 Similarly, IL8 is implicated in cancer cell growth, survival, angiogenesis and metastasis in several tumours. 57 In support, bone marrow plasma and stromal cells from patients with MM were found to secret higher amounts of IL8 than healthy donors; additionally, IL8 up-regulation is involved in MM bone disease and bone marrow angiogenesis.…”

Deregulation of miR‐27a may contribute to canine fibroblast activation after coculture with a mast cell tumour cell line

“…Studies have shown a proproliferative effect of IL‐6 on CAFs and have correlated its expression with increased levels of the CAF marker ACTA2 [55,56]. However, IL‐6 is also an important mediator of a dynamic tumour cell–CAF crosstalk by not only promoting fibroblast activation, but also supporting tumour cell growth in humans [57]. IL‐6 was induced in our PF cocultured with C2 cells, since it was not detectable in control PF or in Exo‐PF cultures.…”