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Lenvatinib suppresses cancer stem-like cells in HCC by inhibiting FGFR1–3 signaling, but not FGFR4 signaling
- Source :
- Carcinogenesis. 42:58-69
- Publication Year :
- 2020
- Publisher :
- Oxford University Press (OUP), 2020.
-
Abstract
- In hepatocellular carcinoma (HCC), a subset of cells defined by high CD44 and CD133 expression has been reported to possess cancer stem-like cell (CSC) characteristics and to be associated with a poor prognosis. Since the approval of the multikinase inhibitor, lenvatinib, for patients with unresectable HCC, two such inhibitors (sorafenib and lenvatinib) have been employed as first-line systemic chemotherapeutics for these patients. Based on differences in the kinase-affinity profiles between these two drugs, evidence has suggested that both exert different effects on HCC, although these differences are not fully characterized. In this study, using in vitro and a preclinical in vivo xenograft mouse model, we showed that lenvatinib alone (not sorafenib or the cytotoxic agent, 5-fluorouracil) diminished CD44High/CD133High CSCs in HCC. Furthermore, western blotting and reverse transcriptase-polymerase chain reaction analysis revealed that the expression of fibroblast growth factor receptor (FGFR)-1–4 differed between CD44High/CD133High CSCs and control cells. Analysis of the effects of selective FGFR inhibitors and FGFR small interfering RNAs on CSCs in HCC revealed that lenvatinib diminished CSCs in HCC by inhibiting FGFR1–3 signaling, however, FGFR4 signaling was not impacted. Finally, we showed that FGF2 and FGF19 were involved in maintaining CD44High/CD133High CSCs in HCC, potentially, via FGFR1–3. The findings provide novel mechanistic insights into the effects of lenvatinib on CSCs in HCC and provide clues for developing effective targeted therapies against CSCs in HCC.
- Subjects :
- 0301 basic medicine
Cancer Research
Cell
Mice
chemistry.chemical_compound
0302 clinical medicine
Molecular Targeted Therapy
biology
Liver Neoplasms
General Medicine
Sorafenib
medicine.anatomical_structure
Fibroblast growth factor receptor
030220 oncology & carcinogenesis
Neoplastic Stem Cells
Quinolines
Female
Fibroblast Growth Factor 2
Fluorouracil
Lenvatinib
Signal Transduction
medicine.drug
Carcinoma, Hepatocellular
03 medical and health sciences
Cell Line, Tumor
medicine
Animals
Humans
Receptor, Fibroblast Growth Factor, Type 3
Receptor, Fibroblast Growth Factor, Type 4
Receptor, Fibroblast Growth Factor, Type 1
Receptor, Fibroblast Growth Factor, Type 2
Protein Kinase Inhibitors
neoplasms
business.industry
Phenylurea Compounds
Fibroblast growth factor receptor 1
CD44
Cancer
Fibroblast growth factor receptor 4
medicine.disease
Xenograft Model Antitumor Assays
digestive system diseases
Fibroblast Growth Factors
030104 developmental biology
chemistry
Cancer research
biology.protein
business
Subjects
Details
- ISSN :
- 14602180 and 01433334
- Volume :
- 42
- Database :
- OpenAIRE
- Journal :
- Carcinogenesis
- Accession number :
- edsair.doi.dedup.....5405705ef4f4d92753b49275146365e5