Co‐expression of c‐kit and stem cell factor in primary and metastatic nasopharyngeal carcinomas and nasopharyngeal epithelium

Sheu, Lai-Fa; Lee, Wen-Cheng; Lee, Herng‐Sheng; Kao, Woei‐Yau; Chen, Ann

doi:10.1002/path.1822

Cited by 22 publications

(14 citation statements)

References 40 publications

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“…In studies that involve metastatic nasopharyngeal carcinoma it was found that activation of SCF/c-Kit signaling potentially contributes to carcinogenesis and progression of this cancer. 37 Finally, in human uveal melanoma the SCF/c-Kit axis was found to play a role in increasing melanoma transformation and proliferation, 37,38 supporting our present studies that this axis may also be important in CCA proliferation.…”

Section: Discussionsupporting

confidence: 73%

Inhibition of Mast Cell-Derived Histamine Decreases Human Cholangiocarcinoma Growth and Differentiation via c-Kit/Stem Cell Factor–Dependent Signaling

Johnson

Huynh

Hargrove

et al. 2016

The American Journal of Pathology

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The tumor microenvironment of cholangiocarcinoma (CCA) is composed of numerous cells, including mast cells (MCs). MCs release histamine, which increases CCA progression and angiogenesis. Cholangiocytes secrete stem cell factor, which functions via the MC growth factor receptor c-Kit. Here, we show that cholangiocytes express histidine decarboxylase and its inhibition reduces CCA growth. MC recruitment in the tumor microenvironment increased CCA growth. MC infiltration and MC markers were detected by toluidine blue staining and real-time PCR in human biopsies and in tumors from athymic mice treated with saline, histamine, histidine decarboxylase inhibitor, or cromolyn sodium. Tumor growth, angiogenesis, and epithelial-mesenchymal transition (EMT)/extracellular matrix (ECM) markers were measured in mice treated with cromolyn sodium. In vitro, human CCA cells were treated with MC supernatant fluids before evaluating angiogenesis and EMT/ECM expression. Migration assays were performed with CCA cells treated with the stem cell factor inhibitor. MC supernatant fluids increased CCA histidine decarboxylase, vascular endothelial growth factor, and MC/EMT/ECM expression that decreased with pretreatment of cromolyn sodium. MCs were found in human biopsies. In mice treated with cromolyn sodium, MC infiltration and tumor growth decreased. Inhibition of CCA stem cell factor blocked MC migration and MC/EMT/ECM in CCA. MCs migrate into CCA tumor microenvironment via c-Kit/stem cell factor and increase tumor progression, angiogenesis, EMT switch, and ECM degradation. Cholangiocarcinoma (CCA) cancers are primary tumors that arise from the neoplastic transformation of cholangiocytes, the epithelial cells lining the intrahepatic and extrahepatic bile ducts of the liver.1 CCA is the second most prevalent liver tumor after hepatocellular carcinoma and accounts for 10% to 20% of deaths caused by hepatobiliary malignancies.2 Increased risk of developing CCA is associated with primary sclerosing cholangitis, liver fluke infestation, hepatitis C virus infection, and other diseases that lead to chronic biliary obstruction and inflammation.3 CAA is a metastatic cancer, and studies have found its potential to migrate outside of the biliary tract. 4 We have found that histamine via the H4 histamine receptor (HR)

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Section: Discussionsupporting

confidence: 73%

Inhibition of Mast Cell-Derived Histamine Decreases Human Cholangiocarcinoma Growth and Differentiation via c-Kit/Stem Cell Factor–Dependent Signaling

Johnson

Huynh

Hargrove

et al. 2016

The American Journal of Pathology

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“…Thus, we need to use a much higher concentration of ApoG2 to kill HONE-1 cells. Also, there may be plenty of other prosurvival molecules, such as c-kit/SCF, 54 that prevent HONE-1 cells from undergoing apoptosis.…”

mentioning

confidence: 99%

ApoG2, a novel inhibitor of antiapoptotic Bcl‐2 family proteins, induces apoptosis and suppresses tumor growth in nasopharyngeal carcinoma xenografts

Zhu

Zhong

et al. 2008

Intl Journal of Cancer

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Nasopharyngeal carcinoma (NPC) is a common malignant tumor in South China. It has been reported that overexpression of antiapoptotic Bcl‐2 family proteins in NPC has caused the lack of long‐term efficacy of conventional therapies. Apogossypolone (ApoG2), a novel small‐molecule inhibitor of antiapoptotic Bcl‐2 family proteins, has been discovered as the optimized derivative of gossypol. In this study, we found that in NPC cells, ApoG2 totally blocked the antiapoptotic function of Bcl‐2 family proteins without affecting the expression levels of these proteins. ApoG2 selectively inhibited proliferation of 3 NPC cell lines (C666‐1, CNE‐1 and CNE‐2) that highly expressed the antiapoptotic Bcl‐2 proteins. This inhibitory activity was associated with release of cytochrome c, activation of caspase‐9 and caspase‐3 and apoptosis of sensitive NPC cells. However, ApoG2 had no obvious inhibitory effect on NPC cell line HONE‐1, which expressed antiapoptotic Bcl‐2 and Bcl‐xL at a low level. We further found that ApoG2 effectively suppressed tumor growth of NPC xenografts in nude mice and enhanced the antitumor effect of CDDP (cisplatin) on NPC cells in vitro and in vivo. Immunohistochemical results showed that the expression of CD31 decreased after ApoG2 treatment, which suggested inhibition of angiogenesis in NPC xenografts. Our findings strongly suggest that ApoG2 may serve as a novel inhibitor of Bcl‐2 family proteins and, by targeting these proteins, may become a promising drug for the treatment of NPC. © 2008 Wiley‐Liss, Inc.

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“…The EBNA1 gene was introduced into the pCP4/EBNA1 plasmid and the control pCP4 vector, and the DNA transfection methods are as previously described (44). The pCP4/EBNA1 plasmid was used to transfect SCM1, TMC1 and LL/2 cells to establish the EBNA1-expressing cells to evaluate the biological effects of EBNA1 in transfected cells.…”

Section: Cells and Animalsmentioning

confidence: 99%

“…Western immunoblotting was used to evaluate EBNA1 expression in tumor masses derived from the tumorigenic assay in nude mice or Balb/c mice as described in a previous report with minor modifications (36,44). In brief, the extracted protein concentration was determined by a bicinchonic acid assay (Pierce, Rockford, IL, USA), and an appropriate amount of protein was used for immunoprecipitation.…”

Section: Immunoprecipitation Of Ebna1 Immunoprecipitation Plusmentioning

confidence: 99%

“…Western immunoblotting was used to evaluate EBNA1 expression in the established EBNA1-expressing SCM1, TMC1 and LL/2 cells, as previously described with minor modifications (44). In brief, blots were incubated with blocking buffer containing 2% BSA, 1% normal goat serum and 0.1% Tween-20 in TBS for 45 min and then incubated with antiserum (at a 1:200 dilution) from an EBV-positive donor with NPC for 2 h. The antigenantibody complex was detected by an HRP-coupled goat anti-human immunoglobulin G (IgG) antibody (Santa Cruz) followed by Western Blotting Luminol Reagent (Santa Cruz).…”

Section: Cells and Animalsmentioning

confidence: 99%

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Expression of Epstein-Barr nuclear antigen 1 in gastric carcinoma cells is associated with enhanced tumorigenicity and reduced cisplatin sensitivity

Cheng

Hsieh²,

Hsu³

et al. 2009

Int J Oncol

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Abstract. Epstein-Barr nuclear antigen 1 (EBNA-1) is consistently expressed in all EBV-associated gastric carcinomas. We explored its biological effects in gastric carcinoma cells by expressing the protein in two Epstein-Barr virus (EBV)-negative gastric carcinoma cell lines (SCM1 and TMC1). EBNA1-expressing SCM1 and TMC1 cells displayed no significant differences in growth rates, respectively, compared to those of vector-transfected SCM1 and TMC1 cells in vitro. However, EBNA1 was able to enhance tumorigenicity, the growth rate and the malignant histopathological grade in a xenograft nude mice test. We also evaluated whether EBNA1 caused EBNA1-expressing cells to have enhanced tumorigenicity in an immunocompetent host. We showed that EBNA1-expressing LL/2 cells (derived from lung carcinoma of a Swiss mouse) had enhanced tumorigenicity and growth ability in the immunocompetent allograft Balb/c mice test. These results support the expression of EBNA1 in EBVassociated gastric carcinoma being able to provide advantages of EBV-mediated cell growth and transformation, and to enhance the malignant potential in vivo. In a clonogenic assay, we showed that EBNA1 could reduce the sensitivity of gastric carcinoma cells (SCM1 cells) harboring wild-type p53 to cisplatin, but this was not found in mutant p53-bearing TMC1 cells. In addition, we demonstrated that EBNA1-expressing SCM1 cells, but not EBNA1-expressing TMC1 cells, were associated with reduced expression levels of p53. These findings are compatible with EBNA1 efficiently competing with p53 for binding to ubiquitin-specific protease 7, which causes p53 to degrade by the ubiquitin/proteasome system. These findings suggest that EBNA1 expression is able to reduce the p53 protein level, resulting in the inhibition of its functional activities. Finally, our results suggest that EBV infection with EBNA1 expression in gastric carcinomas provides advantages for host cell survival, growth ability and transformation potential involving escape from immunosurveillance and a reduction in the sensitivity to DNA damage or other apoptotic stress stimuli mediated by suppression of the wild-type p53 protein level; these are distinct from the pathogenesis of EBV-negative gastric carcinomas. IntroductionGastric carcinoma is a common cancer and results in about 876,000 new cases per year making it one of the leading causes of cancer deaths worldwide (1). Among gastric carcinomas, 2-16% (mean 10%) of conventional gastric adenocarcinomas (2), more than 80% of lymphoepitheliomalike carcinomas (LELCs) of the stomach (3,4), and 35% of adenocarcinomas of the gastric stump are associated with Epstein-Barr virus (EBV) infection (5). The worldwide absolute number of EBV-associated gastric carcinomas makes it the largest group of EBV-associated malignancies (2). This association is characterized by the presence of EBV infection in nearly all tumor cells (6), clonality of the EBV genome in tumor cells and an elevation of EBV-specific antibodies in patients (7,8). The molecular characteristics of E...

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Co‐expression of c‐kit and stem cell factor in primary and metastatic nasopharyngeal carcinomas and nasopharyngeal epithelium

Cited by 22 publications

References 40 publications

Inhibition of Mast Cell-Derived Histamine Decreases Human Cholangiocarcinoma Growth and Differentiation via c-Kit/Stem Cell Factor–Dependent Signaling

Inhibition of Mast Cell-Derived Histamine Decreases Human Cholangiocarcinoma Growth and Differentiation via c-Kit/Stem Cell Factor–Dependent Signaling

ApoG2, a novel inhibitor of antiapoptotic Bcl‐2 family proteins, induces apoptosis and suppresses tumor growth in nasopharyngeal carcinoma xenografts

Expression of Epstein-Barr nuclear antigen 1 in gastric carcinoma cells is associated with enhanced tumorigenicity and reduced cisplatin sensitivity

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