ArticleCellular oncology (Dordrecht, Netherlands)2019
Metformin enhances gefitinib efficacy by interfering with interactions between tumor-associated macrophages and head and neck squamous cell carcinoma cells.
Article in Cellular oncology (Dordrecht, Netherlands), 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.
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Who cites it
37 citing papers in PubMed, 54 citations in OpenAlex.
- GALNT6-glycosylated LRG1 mediates the interaction between M2 macrophages and pancreatic cancer cells by activating CCR1/PI3K/AKT axis.Molecular and cellular biochemistry · 2026Article
- Loop of N2-polarized neutrophils and exhausted CD8 + T cells induces immunotherapy resistance in NSCLC.Molecular and cellular biochemistry · 2026Article
- Metformin modulates the phenotypes of tumor-associated macrophages in glioblastoma in a context-dependent manner by promoting the homeostasis of macrophages.Frontiers in oncology · 2026Article
- Hypoxic Reprogramming of ACOX1-Driven HSP90AB1 Crotonylation Stabilizes Thioredoxin to Orchestrate Redox Homeostasis in Oral Squamous Cell Carcinoma.Research (Washington, D.C.) · 2026Article
- Protein crotonylation in cancer: mechanisms, functions, and therapeutic potential.Cell biology and toxicology · 2025Review
- Biological Anti-Tumoral Mechanisms of Metformin in Head and Neck Squamous Cell Carcinomas: A Systematic Review.Journal of clinical medicine · 2025Review
- Harnessing the tumor microenvironment: targeted cancer therapies through modulation of epithelial-mesenchymal transition.Journal of hematology & oncology · 2025Review
- Fasting-mimicking diet enhances EGFR-TKI efficacy in oral cancer through dual mechanisms: direct cancer cell sensitization and tumor-associated macrophage crosstalk.Frontiers in pharmacology · 2025Article
- The role of the tumor microenvironment in HNSCC resistance and targeted therapy.Frontiers in immunology · 2025Review
- Review
- Natural plant-derived polysaccharides targeting macrophage polarization: a promising strategy for cancer immunotherapy.Frontiers in immunology · 2024Review
- Bridging Chronic Inflammation and Digestive Cancer: The Critical Role of Innate Lymphoid Cells in Tumor Microenvironments.International journal of biological sciences · 2024Review
- CTHRC1 promotes colorectal cancer progression by recruiting tumor-associated macrophages via up-regulation of CCL15.Journal of molecular medicine (Berlin, Germany) · 2024Article
- The mechanisms of action of metformin on head and neck cancer in the pre-clinical setting: a scoping review.Frontiers in oncology · 2024Article
- Alleviating hypoxia to improve cancer immunotherapy.Oncogene · 2023Review
- Survival and Enrichment Analysis of Epithelial-Mesenchymal Transition Genes in Bladder Urothelial Carcinoma.Genes · 2023Article
- Role of chemokines in the crosstalk between tumor and tumor-associated macrophages.Clinical and experimental medicine · 2023Review
- Metformin and cancer hallmarks: shedding new lights on therapeutic repurposing.Journal of translational medicine · 2023Review
- The tumor ecosystem in head and neck squamous cell carcinoma and advances in ecotherapy.Molecular cancer · 2023Review
- Large-Scale Identification of Lysine Crotonylation Reveals Its Potential Role in Oral Squamous Cell Carcinoma.Cancer management and research · 2023Article
Corrections and comments
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Authors and funding
12 authors at 1 institution in 1 country.
Funding
Abstract
backgroundTumor-associated macrophages (TAMs) play an important role in drug resistance in many tumors, including head and neck squamous cell carcinoma (HNSCC). However, how TAMs interact with HNSCC cells to induce drug resistance, especially under hypoxic conditions, is unclear. In this study, we investigated the mechanism of TAM-induced gefitinib resistance in HNSCC cells and sought for novel therapeutic strategies.
methodsThe effects of hypoxia-treated HNSCC cells on the migration and polarization of macrophages were analyzed. Recombinant cytokine proteins and neutralizing antibodies were used as controls. In addition, we assessed the cytotoxic effects of gefitinib on HNSCC cells treated with M2-type macrophage conditioned medium, and carried out a cytokine antibody array analysis, thereby revealing the key factor CCL15. The relationship between serum CCL15 expression levels and prognosis in HNSCC patients was analyzed. In addition, we performed bioinformatic analyses to pursue the mechanisms of CCL15-induced gefitinib resistance. Finally, metformin was used to evaluate the sensitizing effects of gefitinib treatment on HNSCC cells in vitro and in vivo.
resultsWe found that HNSCC cells recruited macrophages by secreting VEGF and polarized the macrophages to the M2 phenotype through IL-6. Conversely, we found that M2-type TAMs promoted HNSCC cell resistance to gefitinib through paracrine CCL15 signaling. The serum CCL15 levels in HNSCC patients showed a significant correlation with patient prognosis. Furthermore, we found that M2-type TAMs could suppress the sensitivity of HNSCC cells to gefitinib through the CCL15-CCR1-NF-κB pathway. In addition, we found that metformin not only inhibited CCL15 expression in M2-type TAMs enhanced by hypoxia, but also suppressed CCR1 surface expression in HNSCC cells. Encouragingly, we found that metformin sensitized HNSCC cells to gefitinib treatment in vitro and in vivo.
conclusionsBased on our data we conclude that we have identified a novel interaction between M2-type TAMs and HNSCC cells that contributes to gefitinib resistance. We also found that metformin inhibited the cross-talk between macrophages and tumor cells, thereby eliciting therapeutic effects both in vitro and in vivo.
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