Lenvatinib suppresses cancer stem-like cells in HCC by inhibiting FGFR 1-3 signaling, but not FGFR4 signaling.

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 multi-kinase 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 RT-PCR analysis revealed that the expression of fibroblast growth factor receptor (FGFR)-1 to 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.

journal_name

Carcinogenesis

journal_title

Carcinogenesis

authors

Shigesawa T,Maehara O,Suda G,Natsuizaka M,Kimura M,Shimazaki T,Yamamoto K,Yamada R,Kitagataya T,Nakamura A,Suzuki K,Ohara M,Kawagishi N,Umemura M,Nakai M,Sho T,Morikawa K,Ogawa K,Ohnishi S,Sugiyama M,Mizokami M,

doi

10.1093/carcin/bgaa049

subject

Has Abstract

pub_date

2020-05-25 00:00:00

eissn

0143-3334

issn

1460-2180

pii

5843707

pub_type

杂志文章
  • A study of endonuclease III-sensitive sites in irradiated DNA: detection of alpha-particle-induced oxidative damage.

    abstract::An important difference between chemical agents that induce oxidative damage in DNA and ionizing radiation is that radiation-induced damage is clustered locally on the DNA. Both modelling and experimental studies have predicted the importance of clustering of lesions induced by ionizing radiation and its dependence on...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/20.5.905

    authors: Prise KM,Pullar CH,Michael BD

    更新日期:1999-05-01 00:00:00

  • Effects of docosahexaenoic acid and eicosapentaenoic acid on androgen-mediated cell growth and gene expression in LNCaP prostate cancer cells.

    abstract::There is some epidemiological support for a protective influence of omega-3 fatty acids against prostate cancer. We wanted to explore whether omega-3 polyunsaturated fatty acids such as docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) can affect androgen receptor function in prostate cancer cells. Our study ...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/22.8.1201

    authors: Chung BH,Mitchell SH,Zhang JS,Young CY

    更新日期:2001-08-01 00:00:00

  • ARA54 is involved in transcriptional regulation of the cyclin D1 gene in human cancer cells.

    abstract::Cyclin D1 is one of the major enhancers of cell cycle progression and its expression is regulated in several growth stimulatory signaling pathways. ARA54 is an androgen receptor (AR) co-activator that enhances AR-dependent transcriptional activation. Although expression of ARA54 mRNA is observed in a variety of human ...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/bgm120

    authors: Kikuchi H,Uchida C,Hattori T,Isobe T,Hiramatsu Y,Kitagawa K,Oda T,Konno H,Kitagawa M

    更新日期:2007-08-01 00:00:00

  • Interactions of cytokine gene polymorphisms in prostate cancer risk.

    abstract::Prostate cancer (CaP) is the second leading cause of cancer death in American men. Chronic inflammation has been one of several factors associated with the development of CaP. Single-nucleotide polymorphisms (SNPs) in cytokine genes have been associated with increased inflammation, increased cytokine production and po...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/bgm277

    authors: Zabaleta J,Lin HY,Sierra RA,Hall MC,Clark PE,Sartor OA,Hu JJ,Ochoa AC

    更新日期:2008-03-01 00:00:00

  • Simple methods for quantifying mutagenic heterocyclic aromatic amines in food products.

    abstract::Two solid-phase extraction methods were developed for the determination of mutagenic heterocyclic aromatic amines in heated meat products. The copper phthalocyanine (CPC) tandem extraction was performed on coupled cartridges of diatomaceous earth and CPC-derivatized Sephasorb HP, followed by further clean-up on Sephas...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/11.9.1597

    authors: Gross GA

    更新日期:1990-09-01 00:00:00

  • A theoretical study of the effect of methylation or ethylation at O6-guanine in the structure and energy of DNA double strands.

    abstract::Quantum and molecular mechanical calculations were employed to examine the effect on binding energies and structure of methylation and ethylation at O6-guanine in double-stranded DNA. Ab initio quantum chemical calculations (STO-3G, 3-21G) were initially used to pseudo-optimize the structure of the 9-methyl derivative...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/9.9.1553

    authors: Pedersen LG,Darden TA,Deerfield DW 2nd,Anderson MW,Hoel DG

    更新日期:1988-09-01 00:00:00

  • Decreased expression of the glutathione S-transferases alpha and pi genes in human renal cell carcinoma.

    abstract::Using the polymerase chain reaction (PCR), a human kidney glutathione S-transferase (GST) alpha cDNA clone (GST alpha 12 K) was synthesized; it is identical to a known liver GST alpha cDNA clone except for one base change (G----A), indicating that an alpha class gene expressed in human kidney is similar to one express...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/11.12.2179

    authors: Klöne A,Weidner U,Hussnätter R,Harris J,Meyer D,Peter S,Ketterer B,Sies H

    更新日期:1990-12-01 00:00:00

  • HGF induces CXCR4 and CXCL12-mediated tumor invasion through Ets1 and NF-kappaB.

    abstract::CXCR4 is a chemokine receptor probably involved in the homing of metastatic breast cancer, and its expression is modulated by tumor environmental stimuli such as hepatocyte growth factor (HGF) and hypoxia. Here, we demonstrate that, depending on the stimulus, different transcription factors can cooperate in enhancing ...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/bgl129

    authors: Maroni P,Bendinelli P,Matteucci E,Desiderio MA

    更新日期:2007-02-01 00:00:00

  • E6AP goes viral: the role of E6AP in viral- and non-viral-related cancers.

    abstract::Since its discovery, the E3 ubiquitin ligase E6-associated protein (E6AP) has been studied extensively in two pathological contexts: infection by the human papillomavirus (HPV), and the neurodevelopmental disorder, Angelman syndrome. Vital biological links between E6AP and other viruses, namely hepatitis C virus and e...

    journal_title:Carcinogenesis

    pub_type: 杂志文章,评审

    doi:10.1093/carcin/bgz072

    authors: Bandilovska I,Keam SP,Gamell C,Machicado C,Haupt S,Haupt Y

    更新日期:2019-07-06 00:00:00

  • Grb2 binding to Tyr284 in TbetaR-II is essential for mammary tumor growth and metastasis stimulated by TGF-beta.

    abstract::We demonstrated previously that growth factor receptor-bound protein 2 (Grb2) associates with the transforming growth factor-beta (TGF-beta) type II receptor [TbetaR-II] upon its phosphorylation on Tyr284 by Src. Although this phosphotransferase reaction is critical in mediating TGF-beta stimulation of epithelial-mese...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/bgm245

    authors: Galliher-Beckley AJ,Schiemann WP

    更新日期:2008-02-01 00:00:00

  • HTLV-1 bZIP factor impedes the menin tumor suppressor and upregulates JunD-mediated transcription of the hTERT gene.

    abstract::Telomerase activity in cancer cells is dependent on the transcriptional regulation of the human telomerase reverse transcriptase (hTERT) gene, encoding the catalytic subunit of human telomerase. We have shown previously that HTLV-1 basic leucine zipper (HBZ), a viral regulatory protein encoded by the human retrovirus,...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/bgt221

    authors: Borowiak M,Kuhlmann AS,Girard S,Gazzolo L,Mesnard JM,Jalinot P,Dodon MD

    更新日期:2013-11-01 00:00:00

  • Cellular background level of 8-oxo-7,8-dihydro-2'-deoxyguanosine: an isotope based method to evaluate artefactual oxidation of DNA during its extraction and subsequent work-up.

    abstract::The measurement of oxidative damage to cellular DNA is a challenging analytical problem requiring highly sensitive and specific methods. In addition, artefactual DNA oxidation during its extraction and subsequent work-up may give rise to overestimated levels of oxidized DNA bases. In the present study, we have used (1...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/23.11.1911

    authors: Ravanat JL,Douki T,Duez P,Gremaud E,Herbert K,Hofer T,Lasserre L,Saint-Pierre C,Favier A,Cadet J

    更新日期:2002-11-01 00:00:00

  • Induction, repair and accumulation of thymine dimers in the skin of UV-B-irradiated hairless mice.

    abstract::A monoclonal antibody specific for cyclobutane thymine dimers in DNA was used in immunofluorescence studies to detect these lesions in skin sections taken from hairless mice that had been irradiated with UV-B. The dimer-specific fluorescence in epidermal cell nuclei was quantified with fluorescence microscopy through ...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/12.5.861

    authors: Vink AA,Berg RJ,de Gruijl FR,Roza L,Baan RA

    更新日期:1991-05-01 00:00:00

  • Sensitivity of the conformation of deoxyguanosine to binding at the C-8 position by N-acetylated and unacetylated 2-aminofluorene.

    abstract::The conformation of N-(deoxyguanosin-8-yl)-2-acetylaminofluorene and N-(deoxyguanosin-8-yl)-2-aminofluorene was investigated by 1H n.m.r. spectroscopy. There was rotation about the glycosyl bond and preference for either the anti or syn conformation depended on whether or not the 8-arylamino nitrogen was acetylated. T...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/1.11.955

    authors: Evans FE,Miller DW,Beland FA

    更新日期:1980-01-01 00:00:00

  • Interaction between functional polymorphic variants in cytokine genes, established risk factors and susceptibility to basal cell carcinoma of skin.

    abstract::Basal cell carcinoma (BCC) of the skin is the most common neoplasm among the Caucasian population of the Western world. Inflammation may result in oxidative stress and contribute to promotion and progression of tumors, including BCC. The role of cytokines, which are inflammatory modulators, in the biology of tumors ha...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/bgr197

    authors: Rizzato C,Canzian F,Rudnai P,Gurzau E,Stein A,Koppova K,Hemminki K,Kumar R,Campa D

    更新日期:2011-12-01 00:00:00

  • Colorectal cancer-derived small extracellular vesicles establish an inflammatory premetastatic niche in liver metastasis.

    abstract::Liver metastases develop in more than half of the patients with colorectal cancer (CRC) and are associated with a poor prognosis. The factors influencing liver metastasis of CRC are poorly characterized, but this information is urgently needed. We have now discovered that small extracellular vesicles (sEVs; exosomes) ...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/bgy115

    authors: Shao Y,Chen T,Zheng X,Yang S,Xu K,Chen X,Xu F,Wang L,Shen Y,Wang T,Zhang M,Hu W,Ye C,Yu X,Shao J,Zheng S

    更新日期:2018-12-13 00:00:00

  • Expression of transforming growth factor alpha/epidermal growth factor receptor, hepatocyte growth factor/c-met and acidic fibroblast growth factor/fibroblast growth factor receptors during hepatocarcinogenesis.

    abstract::It is widely believed that abnormal production of polypeptide growth factors, together with other molecular alterations, play an important role in neoplastic development. Transforming growth factor alpha (TGFalpha), hepatocyte growth factor (HGF) and acidic fibroblast growth factor (aFGF) are the three major growth fa...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/17.5.931

    authors: Hu Z,Evarts RP,Fujio K,Omori N,Omori M,Marsden ER,Thorgeirsson SS

    更新日期:1996-05-01 00:00:00

  • Increased skin carcinogenesis in a keratinocyte directed thioredoxin-1 transgenic mouse.

    abstract::Thioredoxin-1 is a low molecular weight redox protein that protects cells against oxidant damage. Thioredoxin-1 levels are increased in the epidermal layer of sun-damaged human skin. Thioredoxin-1 levels are also increased in several human primary tumors where its expression is associated with increased tumor cell pro...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/bgh195

    authors: Mustacich D,Wagner A,Williams R,Bair W,Barbercheck L,Stratton SP,Bhattacharyya AK,Powis G

    更新日期:2004-10-01 00:00:00

  • Integrated analysis of genetic and epigenetic alterations reveals CpG island methylator phenotype associated with distinct clinical characters of lung adenocarcinoma.

    abstract::DNA methylation affects the aggressiveness of human malignancies. Cancers with CpG island methylator phenotype (CIMP), a distinct group with extensive DNA methylation, show characteristic features in several types of tumors. In this study, we initially defined the existence of CIMP in 41 lung adenocarcinomas (AdCas) t...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/bgs154

    authors: Shinjo K,Okamoto Y,An B,Yokoyama T,Takeuchi I,Fujii M,Osada H,Usami N,Hasegawa Y,Ito H,Hida T,Fujimoto N,Kishimoto T,Sekido Y,Kondo Y

    更新日期:2012-07-01 00:00:00

  • IL-23R in laryngeal cancer: a cancer immunoediting process that facilitates tumor cell proliferation and results in cisplatin resistance.

    abstract::Oncogenic pathogens can disturb tissue homeostasis and initiate immune responses for oncogenicity clearance and homeostasis restoration, while failed clearance and chronic inflammation may result in tumorigenesis. The primary tumor development will undergo a cancer immunoediting process, including three phases, termed...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/bgaa058

    authors: Tao Y,Shen H,Liu Y,Li G,Huang Z,Liu Y

    更新日期:2020-06-12 00:00:00

  • Age-dependent odontogenic lesions in rats after a single i.p. injection of N-nitroso-N-methylurea.

    abstract::The development of a variety of odontogenic lesions was elicited by a single i.p. injection of N-nitroso-N-methylurea (NMU) at a dose of 150 mg/kg body weight. A total of 190 male Wistar/Furth rats were used in this study. The odontogenic lesions appeared macroscopically, mainly as supernumerary lower incisors, 88 +/-...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/4.9.1085

    authors: Smulow JB,Konstantinidis A,Sonnenschein C

    更新日期:1983-09-01 00:00:00

  • 32P-postlabelling of propylene oxide 1- and N(6)-substituted adenine and 3-substituted cytosine/uracil: formation and persistence in vitro and in vivo.

    abstract::Propylene oxide, a widely used monofunctional alkylating agent, has been shown to be genotoxic in in vitro test systems and induces tumors in the nasal tissues of experimental animals. Propylene oxide, like related alkylating agents, forms several different adducts with DNA bases, but predominantly at the 7-position o...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/20.10.2025

    authors: Plna K,Nilsson R,Koskinen M,Segerbäck D

    更新日期:1999-10-01 00:00:00

  • The suppression of aberrant crypt multiplicity in colonic tissue of 1,2-dimethylhydrazine-treated C57BL/6J mice by dietary flavone is associated with an increased expression of Krebs cycle enzymes.

    abstract::Colorectal cancer is the second leading cause of cancer deaths worldwide with diet playing a prominent role in disease initiation and progression. Flavonoids are secondary plant compounds that are suggested as protective ingredients of a diet rich in fruits and vegetables. We here tested whether flavone, a flavonoid t...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/bgm040

    authors: Winkelmann I,Diehl D,Oesterle D,Daniel H,Wenzel U

    更新日期:2007-07-01 00:00:00

  • Effects of green tea catechins in a rat multi-organ carcinogenesis model.

    abstract::The effects of dietary administration of green tea catechins (GTC) were examined using a multi-organ carcinogenesis model. Groups of 15 F344 male rats were initially treated with a single i.p. administration of 100 mg/kg body wt N-diethyl-nitrosamine, 4 i.p. administrations of 20 mg/kg body wt N-methylnitrosourea, 4 s...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/14.8.1549

    authors: Hirose M,Hoshiya T,Akagi K,Takahashi S,Hara Y,Ito N

    更新日期:1993-08-01 00:00:00

  • Genetic susceptibility to lung cancer with special emphasis on CYP1A1 and GSTM1: a study on host factors in relation to age at onset, gender and histological cancer types.

    abstract::Genetically based differences in metabolism, related to MspI restriction site and Ile-Val polymorphisms of the cytochrome P450 (CYP) 1A1 gene and the null genotype of glutathione transferase class mu (GSTM1), have been reported to be associated with lung cancer susceptibility. The present study was set up to establish...

    journal_title:Carcinogenesis

    pub_type: 杂志文章,多中心研究

    doi:10.1093/carcin/15.9.1785

    authors: Alexandrie AK,Sundberg MI,Seidegård J,Tornling G,Rannug A

    更新日期:1994-09-01 00:00:00

  • The principal urinary metabolite of allyl isothiocyanate, N-acetyl-S-(N-allylthiocarbamoyl)cysteine, inhibits the growth and muscle invasion of bladder cancer.

    abstract::Naturally occurring allyl isothiocyanate (AITC) was recently shown to be selectively delivered to bladder cancer tissue via urinary excretion and to inhibit bladder cancer growth and muscle invasion in an animal model. AITC is excreted in urine mainly as N-acetyl-S-(N-allylthiocarbamoyl)cysteine, more commonly known a...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/bgr283

    authors: Bhattacharya A,Li Y,Geng F,Munday R,Zhang Y

    更新日期:2012-02-01 00:00:00

  • MiR-124 targets Slug to regulate epithelial-mesenchymal transition and metastasis of breast cancer.

    abstract::MicroRNAs (miRNAs or miR) have been integrated into tumorigenic programs as either oncogenes or tumor suppressor genes. The miR-124 was reported to be attenuated in several tumors, such as glioma, medulloblastoma and hepatocellular carcinoma. However, its role in cancer remains greatly elusive. In this study, we show ...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/bgs383

    authors: Liang YJ,Wang QY,Zhou CX,Yin QQ,He M,Yu XT,Cao DX,Chen GQ,He JR,Zhao Q

    更新日期:2013-03-01 00:00:00

  • Polymorphisms in genes involved in GH1 release and their association with breast cancer risk.

    abstract::The regulation of growth hormone 1 (GH1) and insulin-like-growth factor-1 (IGF-1) release is under the influence of three pituitary hormones [growth hormone releasing hormone (GHRH), ghrelin (GHRL) and somatostatin (SST)], which act in an autocrine/paracrine fashion in the breast. By binding to their respective recept...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/bgl036

    authors: Wagner K,Hemminki K,Grzybowska E,Klaes R,Burwinkel B,Bugert P,Schmutzler RK,Wappenschmidt B,Butkiewicz D,Pamula J,Pekala W,Försti A

    更新日期:2006-09-01 00:00:00

  • AFF4 promotes tumorigenesis and tumor-initiation capacity of head and neck squamous cell carcinoma cells by regulating SOX2.

    abstract::Super elongation complex (SEC) controls gene transcription by releasing Pol II from pausing. Previous studies have shown that dysfunction of SEC was associated with multiple human cancers, such as leukemia and breast cancer. However, the role of SEC in head and neck squamous cell carcinoma (HNSCC) development remains ...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/bgy046

    authors: Deng P,Wang J,Zhang X,Wu X,Ji N,Li J,Zhou M,Jiang L,Zeng X,Chen Q

    更新日期:2018-07-03 00:00:00

  • A Large-scale genetic association study of esophageal adenocarcinoma risk.

    abstract::The incidence of esophageal adenocarcinoma (EA) has been increasing rapidly, particularly among white males, over the past few decades in the USA. However, the etiology of EA and the striking male predominance is not fully explained by known risk factors. To identify susceptible genes for EA risk, we conducted a pathw...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/bgq092

    authors: Liu CY,Wu MC,Chen F,Ter-Minassian M,Asomaning K,Zhai R,Wang Z,Su L,Heist RS,Kulke MH,Lin X,Liu G,Christiani DC

    更新日期:2010-07-01 00:00:00