ArticleCancer communications (London, England)2023
Tumor-derived insulin-like growth factor-binding protein-1 contributes to resistance of hepatocellular carcinoma to tyrosine kinase inhibitors.
Article in Cancer communications (London, England), 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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14 citing papers in PubMed, 21 citations in OpenAlex.
- Insulin-like growth factor receptor signaling in physiology and disease.Signal transduction and targeted therapy · 2026Review
- Combined Exposure to 1,2-Dichloropropane and Dichloromethane Enhances Hepatocellular Tumor Development in Mice.Toxics · 2026Article
- Dihydroartemisinin exerts antitumour activity by blocking SIRT2-IGFBP1-induced PI3K/AKT/mTOR signal transduction in liver cancer.Scientific reports · 2026Article
- Recent advances in biomarkers for cardiac fibrosis.Frontiers in cardiovascular medicine · 2026Review
- IGFBP1 is a prognostic biomarker in esophageal carcinoma: mechanistic insights from bioinformatics profiling toFrontiers in immunology · 2026Article
- D-amino acid oxidase suppresses hepatocellular carcinoma via oxidizing D-amino acids.Journal of translational medicine · 2025Article
- Pathologic Signaling and Disease Implications of Insulin-like Growth Factor Binding Proteins in Cancer, Cardiovascular Disease, and Fibrosis.International journal of molecular sciences · 2025Review
- Insulin‑like growth factor in cancer: New perspectives (Review).Molecular medicine reports · 2025Review
- SNRPB/CCNB1 axis promotes hepatocellular carcinoma progression and cisplatin resistance through enhancing lipid metabolism reprogramming.Journal of experimental & clinical cancer research : CR · 2025Article
- Paradoxical Effect of Myosteatosis on the Immune Checkpoint Inhibitor Response in Metastatic Renal Cell Carcinoma.Journal of cachexia, sarcopenia and muscle · 2025Article
- Lenvatinib and immune-checkpoint inhibitors in hepatocellular carcinoma: mechanistic insights, clinical efficacy, and future perspectives.Journal of hematology & oncology · 2024Review
- The Immune Inductive Role of Hepatic Arterial Infusion Chemotherapy Prior to Atezolizumab Plus Bevacizumab Combination Therapy in Hepatocellular Carcinoma.Gastro hep advances · 2024Review
- Efficacy of Lenvatinib Combined with Transcatheter Intra-Arterial Therapies for Patients with Advanced-Stage of Hepatocellular Carcinoma: A Propensity Score Matching.International journal of molecular sciences · 2023Article
- Tumor-derived insulin-like growth factor-binding protein-1 contributes to resistance of hepatocellular carcinoma to tyrosine kinase inhibitors.Cancer communications (London, England) · 2023Article
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Authors and funding
23 authors at 3 institutions in 2 countries.
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No grant is acknowledged in the PubMed record.
Abstract
backgroundAntiangiogenic tyrosine kinase inhibitors (TKIs) provide one of the few therapeutic options for effective treatment of hepatocellular carcinoma (HCC). However, patients with HCC often develop resistance toward antiangiogenic TKIs, and the underlying mechanisms are not understood. The aim of this study was to determine the mechanisms underlying antiangiogenic TKI resistance in HCC.
methodsWe used an unbiased proteomic approach to define proteins that were responsible for the resistance to antiangiogenic TKIs in HCC patients. We evaluated the prognosis, therapeutic response, and serum insulin-like growth factor-binding protein-1 (IGFBP-1) levels of 31 lenvatinib-treated HCC patients. Based on the array of results, a retrospective clinical study and preclinical experiments using mouse and human hepatoma cells were conducted. Additionally, in vivo genetic and pharmacological gain- and loss-of-function experiments were performed.
resultsIn the patient cohort, IGFBP-1 was identified as the signaling molecule with the highest expression that was inversely associated with overall survival. Mechanistically, antiangiogenic TKI treatment markedly elevated tumor IGFBP-1 levels via the hypoxia-hypoxia inducible factor signaling. IGFBP-1 stimulated angiogenesis through activation of the integrin α5β1-focal adhesion kinase pathway. Consequently, loss of IGFBP-1 and integrin α5β1 by genetic and pharmacological approaches re-sensitized HCC to lenvatinib treatment.
conclusionsTogether, our data shed light on mechanisms underlying acquired resistance of HCC to antiangiogenic TKIs. Antiangiogenic TKIs induced an increase of tumor IGFBP-1, which promoted angiogenesis through activating the IGFBP-1-integrin α5β1 pathway. These data bolster the application of a new therapeutic concept by combining antiangiogenic TKIs with IGFBP-1 inhibitors.
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