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Acquisition of mesenchymal-like phenotypes and overproduction of angiogenic factors in lenvatinib-resistant hepatocellular carcinoma cells.

Authors:
Junjie Ao Tetsuhiro Chiba Shuhei Shibata Akane Kurosugi Na Qiang Yaojia Ma Motoyasu Kan Terunao Iwanaga Takafumi Sakuma Hiroaki Kanzaki Kengo Kanayama Ryuta Kojima Yuko Kusakabe Masato Nakamura Tomoko Saito Ryo Nakagawa Takayuki Kondo Sadahisa Ogasawara Eiichiro Suzuki Ryosuke Muroyama Jun Kato Naoya Mimura Tatsuo Kanda Hitoshi Maruyama Naoya Kato

Biochem Biophys Res Commun 2021 Apr 3;549:171-178. Epub 2021 Mar 3.

Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan.

Lenvatinib is one of the first-line drugs for patients with advanced hepatocellular carcinoma (HCC) and widely used around the world. However, the mechanisms underlying resistance to lenvatinib remain unclear. In this study, we conducted characteristic analyses of lenvatinib-resistant HCC cells. Lenvatinib-resistant HCC cell lines were established by exposure to serially escalated doses of lenvatinib over 2 months. The biological characteristics of these cells were examined by in vitro assays. To investigate the cytokine profile of lenvatinib-resistant HCC cells, the supernatant derived from lenvatinib-resistant Huh7 cells was subjected to nitrocellulose membrane-based sandwich immunoassay. Both activation of the MAPK/MEK/ERK signaling pathway and upregulation of epithelial mesenchymal transition markers were observed in lenvatinib-resistant cells. Concordant with these findings, proliferation and invasion abilities were enhanced in these cells compared with control cells. Screening of a cytokine array spotted with 105 different antibodies to human cytokines enabled us to identify 16 upregulated cytokines in lenvatinib-resistant cells. Among them, 3 angiogenic cytokines: vascular endothelial growth factor (VEGF), platelet-derived growth factor-AA (PDGF-AA), and angiogenin, were increased significantly. Conditioned medium from lenvatinib-resistant cells accelerated tube formation of human umbilical vein cells. In conclusion, lenvatinib-resistant HCC cells were characterized by enhanced proliferation and invasion abilities. These findings might contribute to the establishment of new combination therapies with lenvatinib.

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http://dx.doi.org/10.1016/j.bbrc.2021.02.097DOI Listing
April 2021

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Acquisition of mesenchymal-like phenotypes and overproduction of angiogenic factors in lenvatinib-resistant hepatocellular carcinoma cells.

Authors:
Junjie Ao Tetsuhiro Chiba Shuhei Shibata Akane Kurosugi Na Qiang Yaojia Ma Motoyasu Kan Terunao Iwanaga Takafumi Sakuma Hiroaki Kanzaki Kengo Kanayama Ryuta Kojima Yuko Kusakabe Masato Nakamura Tomoko Saito Ryo Nakagawa Takayuki Kondo Sadahisa Ogasawara Eiichiro Suzuki Ryosuke Muroyama Jun Kato Naoya Mimura Tatsuo Kanda Hitoshi Maruyama Naoya Kato

Biochem Biophys Res Commun 2021 Apr 3;549:171-178. Epub 2021 Mar 3.

Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan.

Lenvatinib is one of the first-line drugs for patients with advanced hepatocellular carcinoma (HCC) and widely used around the world. However, the mechanisms underlying resistance to lenvatinib remain unclear. In this study, we conducted characteristic analyses of lenvatinib-resistant HCC cells. Read More

View Article and Full-Text PDF
April 2021
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Clin Cancer Res 2021 Feb 7;27(4):1150-1161. Epub 2020 Dec 7.

Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan.

Purpose: Hepatocellular carcinoma (HCC) is characterized by high intertumor heterogeneity of genetic drivers. Two multitarget tyrosine kinase inhibitors (TKI), lenvatinib and sorafenib, are used as standard-of-care chemotherapeutics in patients with advanced HCC, but a stratification strategy has not been established because of a lack of efficacious biomarkers. Therefore, we sought biomarkers that indicate lenvatinib-susceptible HCC. Read More

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Sophoridine suppresses lenvatinib-resistant hepatocellular carcinoma growth by inhibiting RAS/MEK/ERK axis via decreasing VEGFR2 expression.

Authors:
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J Cell Mol Med 2021 Jan 18;25(1):549-560. Epub 2020 Nov 18.

Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, the Fifth Affiliated Hospital of Wenzhou Medical University /Affiliated Lishui Hospital of Zhejiang University/ The Central Hospital of Zhejiang Lishui, Lishui, China.

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Oxysophocarpine suppresses FGFR1-overexpressed hepatocellular carcinoma growth and sensitizes the therapeutic effect of lenvatinib.

Authors:
Zhongwei Zhao Jingjing Song Dengke Zhang Fazong Wu Jianfei Tu Jiansong Ji

Life Sci 2021 Jan 24;264:118642. Epub 2020 Oct 24.

Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, the Fifth Affiliated Hospital of Wenzhou Medical University/Affiliated Lishui Hospital of Zhejiang University/The Central Hospital of Zhejiang Lishui, Lishui 323000, China; Department of Radiology, the Fifth Affiliated Hospital of Wenzhou Medical University/Affiliated Lishui Hospital of Zhejiang University/The Central Hospital of Zhejiang Lishui, Lishui 323000, China. Electronic address:

Aims: Hepatocellular carcinoma (HCC) is an aggressive solid tumor with restricted therapeutics. Lenvatinib is the second approved frontline drug for advanced HCC, however lenvatinib-resistant cases have been reported in clinical. Overexpression of fibroblast growth factor receptor (FGFR1) has been found to be associated with advanced HCC. Read More

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January 2021
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