The natural agent 4-vinylphenol targets metastasis and stemness features in breast cancer stem-like cells
Background and purpose
Cancer stem-like cells (CSC) are regarded as the source of tumour origins, metastasis and drug resistance, and limits current treatment regimens. Previously, we reported the first study of the anti-angiogenic and anti-tumour activities of 4-vinylphenol. To further examine the therapeutic role of 4-vinylphenol, the inhibitory effects of 4-vinylphenol on cancer stemness, drug resistance and metastasis in breast cancer were investigated in the present study.
Study design and methods
We enriched parental MDA-MB-231 cells with CSCs in serum-free medium to give spheroids. The effects of 4-vinylphenol on cancer stemness, metastasis and drug resistance in CSC-enriched MDA-MB-231 cells were studied in vitro and in vivo.
CSC-enriched MDA-MB-231 cells demonstrated higher tumorigenic and metastatic potential. 4-Vinylphenol reduced spheroid formation and ALDH1 expression in CSC-enriched cultures, revealing its inhibitory effects on the traits of CSCs. 4-Vinylphenol suppressed colony formation and cell proliferation. 4VP also inhibited in vitro invasion and in vivo metastasis in zebrafish model. Our results showed that it reduced vimentin expression, suppressed cell migration, affected the expression and/or activity of MMPs, TIMPs and uPA. In addition, the expressions of caspases 3 and 9 were increased upon its treatment, and surprisingly, prolonged treatment did not confer cancer cells with drug resistance to 4-vinylphenol. 4-Vinylphenol probably exhibited its anti-cancer activities via beta-catenin, EGFR and AKT signaling pathways.
4-Vinylphenol was shown to inhibit metastasis and cancer stemness in CSC-enriched breast cancer cells. Since conventional therapies not targeting CSCs possibly lead to failure to eliminate cancer, 4-vinylphenol is a highly potential therapeutic agent for breast cancer patients.
KeywordsCancer stem-like cells Breast cancer 4-Vinylphenol Metastasis Drug resistance Tumorigenicity
Cancer stem-like cell
Chemokine receptor-type 4
Epidermal growth factor receptor
Focal adhesion kinase
3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide
Tissue inhibitor of matrix metalloproteinase
Urokinase-type plasminogen activator
The authors would like to thank Mr. Ching-Po Lau, Miss Xiaoxiao Wu and Miss Julia Lee for their technical support.
HWL designed the study, performed in vitro and in vivo experiments, analyzed data, and drafted the manuscript; CHK and GGLY designed the study and revised the manuscript; IH provided technical support on cancer stem cell study and CBSL was in-charge and supervised the project and revised the manuscript. All authors discussed the results and commented on the manuscript at all stages.
This study was partly supported by grants of the State Key Laboratory of Phytochemistry and Plant Resources in West China (CUHK) from Innovation and Technology Commission, HKSAR, and the Chinese University of Hong Kong.
Compliance with ethical standards
Conflict of interest
Dr. Leung declares that she has no conflict of interest. Dr. Ko declares that he has no conflict of interest. Dr. Yue declares that she has no conflict of interest. Prof. Herr declares that she has no conflict of interest. Prof. Lau declares that she has no conflict of interest.
All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All experimental protocols were approved by the Animal Experimentation Ethics Committee of The Chinese University of Hong Kong with reference numbers Ref No. 15/128/MIS and 16/162/MIS.
Research involving human and animal participants
This article does not contain any studies with human participants performed by any of the authors.
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