ArticleProceedings of the National Academy of Sciences of the United States of America2018
Hypoxic tumor microenvironment activates GLI2 via HIF-1α and TGF-β2 to promote chemoresistance in colorectal cancer.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 197 papers.
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Who cites it
197 citing papers in PubMed, 269 citations in OpenAlex.
- Review
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- Autophagy Orchestrates Anti-Tumor Immunity to Enhance Chemosensitivity via the FBXW2/C/EBPβ/TIMP-2 Axis in Colorectal Cancer.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Review
- Cancer Stem Cells in Colorectal Cancer: From Molecular Mechanisms to Diagnosis, Prognosis and Therapy Implications.Cancers · 2026Review
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- The extracellular matrix: structure, composition, biological functions, diseases, and therapeutic targets.Molecular biomedicine · 2026Review
- Hypoxia facilitates triple-negative breast cancer stem cells enrichment and stemness maintenance through oxidized ataxia telangiectasia mutated-induced one-carbon metabolism.World journal of stem cells · 2026Article
- Loss of KDM6A-mediated genomic instability and metabolic reprogramming regulates response to therapeutic perturbations in bladder cancer.Nature communications · 2026Article
- The central regulator HIF-1α in digestive system pathologies: inflammation and cancer.Frontiers in immunology · 2026Review
- Single-cell multi-omics characterize colorectal tumors, adjacent healthy tissue and matched (tumor) organoids identifying CRC-unique features.International journal of cancer · 2025Article
- Targeting asymmetric division in cancer stem cells: implications for relapse and resistance.Cancer cell international · 2025Review
- Fibroblasts in the tumor microenvironment: heterogeneity and dynamic interactions in tumor progression revealed by spatial transcriptomics.Cellular oncology (Dordrecht, Netherlands) · 2025Review
- Colorectal Cancer at the Crossroads: The Good, the Bad, and the Future of Platinum-Based Drugs.Chemical reviews · 2025Review
- Model for Predicting Serious Hematological Adverse Events in Individuals With Ovarian Cancer Receiving Poly (Adenosine Diphosphate Ribose) Polymerase Inhibitor Treatment: Prospective Cohort Study.JMIR medical informatics · 2025Article
- Hedgehog pathway, cell cycle, and primary cilium.Cell death discovery · 2025Review
- Co-delivery of Liposomal Ketoconazole and Bevacizumab for Synergistical Inhibition of Angiogenesis Against Endometrial Cancer.Molecular biotechnology · 2025Article
- Elucidating the tumor microenvironment interactions in breast, cervical, and ovarian cancer through single-cell RNA sequencing.Scientific reports · 2025Article
- Targeting theBiomedicines · 2025Article
- GLI2 Facilitates Tumor Immune Evasion and Immunotherapeutic Resistance by Coordinating WNT and Prostaglandin Signaling.Cancer research · 2025Article
137 more citing papers are in PubMed but not listed here.
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Authors and funding
15 authors at 6 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Colorectal cancer patients often relapse after chemotherapy, owing to the survival of stem or progenitor cells referred to as cancer stem cells (CSCs). Although tumor stromal factors are known to contribute to chemoresistance, it remains not fully understood how CSCs in the hypoxic tumor microenvironment escape the chemotherapy. Here, we report that hypoxia-inducible factor (HIF-1α) and cancer-associated fibroblasts (CAFs)-secreted TGF-β2 converge to activate the expression of hedgehog transcription factor GLI2 in CSCs, resulting in increased stemness/dedifferentiation and intrinsic resistance to chemotherapy. Genetic or small-molecule inhibitor-based ablation of HIF-1α/TGF-β2-mediated GLI2 signaling effectively reversed the chemoresistance caused by the tumor microenvironment. Importantly, high expression levels of HIF-1α/TGF-β2/GLI2 correlated robustly with the patient relapse following chemotherapy, highlighting a potential biomarker and therapeutic target for chemoresistance in colorectal cancer. Our study thus uncovers a molecular mechanism by which hypoxic colorectal tumor microenvironment promotes cancer cell stemness and resistance to chemotherapy and suggests a potentially targeted treatment approach to mitigating chemoresistance.
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