The heterogeneity of cancer-associated fibroblasts (CAFs) might be ascribed to differences in origin. CD10 and GPR77 have been reported to identify a chemoresistance-inducing CAF subset in breast cancer. However, the precise mechanism for the formation of the CD10+GPR77+ CAFs remains unknown. In this study, we found that CCL18 expression was positively correlated with the density of CD10+GPR77+ CAFs in breast cancer and associated with a poor response to chemotherapy. Moreover, CCL18 secreted by tumor-associated macrophages (TAMs) activated a CD10+GPR77+ CAF phenotype in normal breast-resident fibroblasts (NBFs), which could then enrich cancer stem cells (CSCs) and induce chemoresistance in breast cancer cells. Mechanistically, CCL18 activated NF-κB signaling via PITPNM3 and thus enhanced the production of IL-6 and IL-8. Furthermore, intratumoral CCL18 injection significantly induced the activation of NBFs and the chemoresistance of xenografts in vivo. In addition, targeting CCL18 by anti-CCL18 antibody could inhibit the formation of CD10+GPR77+ CAFs and recover the chemosensitivity in vivo, leading to effective tumor control. Collectively, these findings reveal that inflammatory signaling crosstalk between TAMs and fibroblasts is responsible for the formation of the CD10+GPR77+ CAFs, suggesting CCL18–PITPNM3 signaling is a potential therapeutic target to block the activation of this specific CAF subtype and tumor chemoresistance.
Background:
The Compound Sophora flavescenes (Kushen) Decoction was found to reduce the inflammatory symptom of Ulcerative colitis (UC). However, there exists a very limited understanding of the molecular pharmacological mechanisms.
Objective:
To explore the mechanism of Compound Sophora flavescens (Kushen) Decoction in treating ulcerative colitis from the perspective of network pharmacology.
Methods:
Active components and potential targets of Compound Sophora flavescens (Kushen) Decoction were obtained through the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) database. GeneCards and other databases were used to predict and screen ulcerative colitis related genes. Cytoscape software was applied to construct “drug-active component-disease-target” network. GO function and KEGG pathway enrichment analysis revealed the potential pathway of the Compound Sophora flavescenes (Kushen) Decoction for UC.
Results:
After screening, a total of 124 active ingredients and 163 potential therapeutic targets for UC, were obtained for the Compound Sophora flavescens (Kushen) Decoction. Protein interaction network analysis showed that 15 key targets could be identified for the possible treatment of UC. GO and KEGG analysis showed that the active ingredients in the Compound Sophora flavescens (Kushen) Decoction were mainly enriched in 2556 biological processes and 172 signaling pathways.
Conclusion:
The study showed that the Compound Sophora flavescens (Kushen) Decoction has therapeutic effects on UC through multi-component, multi-target, and multi-pathway.
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