ArticleCancer communications (London, England)2023
Cancer-associated fibroblast-derived secreted phosphoprotein 1 contributes to resistance of hepatocellular carcinoma to sorafenib and lenvatinib.
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 135 papers, 1 of them a synthesis that pooled it.
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Who cites it
135 citing papers in PubMed, 1 synthesis or guideline pooled it, 169 citations in OpenAlex.
- Pooled it
- Efficacy and safety of lenvatinib plus gefitinib in lenvatinib-resistant hepatocellular carcinomas: a prospective, single-arm exploratory trial.Signal transduction and targeted therapy · 2024Trial
- HKDC1 as a Prognostic and Tumor Microenvironment‑Associated Biomarker in Colorectal Cancer: An Integrated Multi‑omics and Spatial Transcriptomic Study.Digestive diseases and sciences · 2026Article
- Cancer-associated fibroblasts in therapeutic resistance of hepatocellular carcinoma: evidence, mechanisms, and translational implications.Medical oncology (Northwood, London, England) · 2026Review
- Multi-omic analysis of jaw-bone periosteum identifies the role of macrophage-derived SPP1 in CtskBone research · 2026Article
- Modulation of the tumor microenvironment through BMAL1-LHX8 axis augments the sensitivity of ameloblastoma to vemurafenib.Journal of advanced research · 2026Article
- Cancer-Associated Fibroblasts Promote Glucose Metabolic Reprogramming and Progression of Triple-Negative Breast Cancer via Exosomal circFAD104-Mediated Intercellular Communication.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Dual-modular-nanobody CAR-T cell technical platform against the solid tumor microenvironment.Journal of hematology & oncology · 2026Article
- Clinical significance of secreted phosphoprotein-1 overexpression in cancers.International journal of clinical oncology · 2026Article
- Exosome Secretion Drives Chemo-Resistance of Temozolomide in Glioblastoma.Journal of extracellular biology · 2026Article
- Cancer-Associated Fibroblasts Promote Tumor Immunosuppression in Hepatocellular Carcinoma via the NNMT-ANGPTL4 Axis.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Targeting ferroptosis induction via nanomaterials in hepatocellular carcinoma: an insight into mechanism and therapeutic potential.Journal of nanobiotechnology · 2026Review
- 3D bioprinting for cancer modeling and drug screening.Biomarker research · 2026Review
- Tumor-derived WNT7A reprograms pulmonary fibroblasts to remodel the metastatic niche and promote bladder cancer lung metastasis.Experimental & molecular medicine · 2026Article
- Activation of methionine metabolism mediated by HNF4α confers ferroptosis resistance in hepatocellular carcinoma.Cell death discovery · 2026Article
- PHKG2 confers resistance of ESCC to cisplatin and enhances CXCL8-dependent immunosuppression to exacerbate tumorigenesis.Cell death & disease · 2026Article
- Plasma interleukin-8 as a predictive biomarker for tyrosine kinase inhibitor response in advanced hepatocellular carcinoma.Discover oncology · 2026Article
- Protein expression profiling of lenvatinib-resistant liver cancer cells and identify B4GALT4 as a critical drug resistance molecule.Discover oncology · 2026Article
- Review
- Targeting intrinsic and CAF-mediated signaling by PI3Kα inhibitor CYH33 attenuated metastasis in lung squamous cell carcinoma.Acta pharmacologica Sinica · 2026Article
75 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
15 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundCancer-associated fibroblasts (CAFs) play an important role in the induction of chemo-resistance. This study aimed to clarify the mechanism underlying CAF-mediated resistance to two tyrosine kinase inhibitors (TKIs), sorafenib and lenvatinib, and to identify a novel therapeutic target for overcoming TKI resistance in hepatocellular carcinoma (HCC).
methodsWe performed a systematic integrative analysis of publicly available gene expression datasets and whole-transcriptome sequencing data from 9 pairs of CAFs and para-cancer fibroblasts isolated from human HCC and para-tumor tissues, respectively, to identify key molecules that might induce resistance to TKIs. We then performed in vitro and in vivo experiments to validate selected targets and related mechanisms. The associations of plasma secreted phosphoprotein 1 (SPP1) expression levels before sorafenib/lenvatinib treatment with progression-free survival (PFS) and overall survival (OS) of 54 patients with advanced HCC were evaluated using Kaplan-Meier and Cox regression analysis.
resultsBioinformatic analysis identified CAF-derived SPP1 as a candidate molecule driving TKI resistance. SPP1 inhibitors reversed CAF-induced TKI resistance in vitro and in vivo. CAF-derived SPP1 activated rapidly accelerated fibrosarcoma (RAF)/mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) through the integrin-protein kinase C-alpha (PKCα) signaling pathway and promoted epithelial-to-mesenchymal transition (EMT). A high plasma SPP1 level before TKI treatment was identified as an independent predictor of poor PFS (P = 0.026) and OS (P = 0.047) in patients with advanced HCC after TKI treatment.
conclusionsCAF-derived SPP1 enhances TKI resistance in HCC via bypass activation of oncogenic signals and EMT promotion. Its inhibition represents a promising therapeutic strategy against TKI resistance in HCC. Moreover, plasma SPP1 level before TKI treatment represents a potential biomarker for treatment response prediction.
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