IL6 derived from cancer-associated fibroblasts promotes chemoresistance via CXCR7 in esophageal squamous cell carcinoma

Abstract

Various factors and cellular components in the tumor microenvironment are key drivers associated with drug resistance in many cancers. Here, we analyzed the factors and molecular mechanisms involved in chemoresistance in patients with esophageal squamous cell carcinoma (ESCC). We found that interleukin 6 (IL6) derived mainly from cancer-associated fibroblasts played the most important role in chemoresistance by upregulating C-X-C motif chemokine receptor 7 (CXCR7) expression through signal transducer and activator of transcription 3/nuclear factor-κB pathway. CXCR7 knockdown resulted in the inhibition of IL6-induced proliferation and chemoresistance. In addition, CXCR7 silencing significantly decreased gene expression associated with stemness, chemoresistance and epithelial-mesenchymal transition and suppressed the proliferation ability of ESCC cells in three-dimensional culture systems and angiogenesis assay. In clinical samples, ESCC patients with high expression of CXCR7 and IL6 presented a significantly worse overall survival and progression-free survival upon receiving cisplatin after operation. These results suggest that the IL6-CXCR7 axis may provide a promising target for the treatment of ESCC.

Chloroquine Inhibits Stemness of Esophageal Squamous Cell Carcinoma Cells Through Targeting CXCR4-STAT3 Pathway

“…The prognosis for ESCC remains poor largely due to late diagnosis and propensity for metastasis. Despite significant advances in diagnostic techniques and therapeutic approaches, the overall 5-year survival rate ranges from 15 to 25% (3)(4)(5). Recent studies have shown that many malignancies contain a cell subpopulation known as cancer stem cells (CSCs), which are thought to cause aggressive tumor behavior and therapy resistance and have high tumor-initiating capacity, thereby leading to recurrence, metastasis, and insufficient response to conventional therapies (6).…”

Mesenchymal stromal cells release CXCL1/2/8 and induce chemoresistance and macrophage polarization

“…Here we characterized precisely the mechanisms by which CA-MSCs exert their biological functions, in particular the role played by the cytokines produced by these cells (CXCR1/2 ligands). We studied the role played by these ligands, while several other authors have mainly focused their attentions on IL-6 and its role in cancer cell proliferation [17,44,45].…”

Extracellular Matrix in the Tumor Microenvironment and Its Impact on Cancer Therapy

“…CAFs already contribute to chemoresistance by themselves via various mechanisms: PAI-1, a cytokine produced by CAFs, activates Erk/Akt signaling and suppresses caspase-3 activation, which is necessary for tumor apoptosis following chemotherapeutic stress (Che et al, 2018). Similarly, interleukin 6 (IL6) is also produced predominantly by CAFs and induces expression of resistance-mediating CXCR7 in tumor cells (Qiao et al, 2018;Xu et al, 2018). Especially under hypoxic conditions, CAFs produce high levels of TGFβ, which induces stem celllike properties in tumor cells including increased resistance to chemotherapy (Tang et al, 2018).…”