nach oben

Erschienen in:

01.07.2013 | Original Article—Alimentary Tract

Chimeric 5/35 adenovirus-mediated Dickkopf-1 overexpression suppressed tumorigenicity of CD44⁺ gastric cancer cells via attenuating Wnt signaling

verfasst von: Bin Wang, Jia Liu, Lei Na Ma, Hua Liang Xiao, Ya Zhou Wang, Yan Li, Zhe Wang, Linli Fan, Chunhui Lan, Min Yang, Lu Hu, Yanlin Wei, Xiu Wu Bian, Dongfeng Chen, Jun Wang

Erschienen in: Journal of Gastroenterology | Ausgabe 7/2013

Einloggen, um Zugang zu erhalten

Abstract

Background

Gastric cancer stem cells (CSCs), which require activation of Wnt signaling to maintain their self-renewal and tumorigenicity, are proposed to be critical targets for effective therapy of gastric carcinomas. Gene therapies that are delivered by adenovirus of serotype 5 (Ad5) or chimeric 5/35(Ad5/35) adenovirus have shown promise for treating various cancers. Here we aimed to develop a gene therapy strategy that targeted gastric CSCs (CD44⁺ cells).

Methods

CD44⁺ cells were isolated by fluorescence activated cell sorting from both primary gastric cancer cells and cell lines. Expression of adenovirus receptors was examined in CD44⁺ and CD44⁻ cells. A potent Wnt antagonist Dickkopf-1 (DKK1) was delivered into CD44⁺ cells using Ad5/35 (Ad5/35-DKK1). The therapeutic outcomes were evaluated.

Results

Expression of Coxsakievirus adenovirus receptor for Ad5 was significantly reduced, while abundance of CD46, the receptor for Ad5/35, was slightly higher in CD44⁺ cells. Accordingly, CD44⁺ cells were sensitive to Ad5/35 infection, but not to Ad5. Ad5/35-DKK1 introduced DKK1 into CD44⁺ cells and deactivated endogenous Wnt/β-catenin signaling efficiently. Overexpression of DKK1 inhibited survival, anchorage-independent colony formation, and invasion of CD44⁺ cells, which were restored by a GSK-3 specific inhibitor BIO-acetoxime. More importantly, introduction of DKK1 abrogated the tumorigenicity of CD44⁺ cells in vivo. However, Ad5/35-DKK1 only showed minimal cytotoxicity to normal tissue-derived cells, L-02 and GES-1.

Conclusions

We developed, for the first time, a novel Ad5/35-DKK1-based approach to abrogate Wnt signaling in CSCs and demonstrated that gastric CSC-targeting gene therapy was effective in preclinical experiments.

Nur mit Berechtigung zugänglich

Bertuccio P, Chatenoud L, Levi F, Praud D, Ferlay J, Negri E, et al. Recent patterns in gastric cancer: a global overview. Int J Cancer. 2009;125:666–73.PubMedCrossRef

Dewi DL, Ishii H, Kano Y, Nishikawa S, Haraguchi N, Sakai D, et al. Cancer stem cell theory in gastrointestinal malignancies: recent progress and upcoming challenges. J Gastroenterol. 2011;46:1145–57.PubMedCrossRef

Zhou BB, Zhang H, Damelin M, Geles KG, Grindley JC, Dirks PB. Tumour-initiating cells: challenges and opportunities for anticancer drug discovery. Nat Rev Drug Discov. 2009;8:806–23.PubMedCrossRef

Ishimoto T, Oshima H, Oshima M, Kai K, Torii R, Masuko T, et al. CD44⁺ slow-cycling tumor cell expansion is triggered by cooperative actions of Wnt and prostaglandin E2 in gastric tumorigenesis. Cancer Sci. 2010;101:673–8.PubMedCrossRef

Takaishi S, Okumura T, Tu S, Wang SS, Shibata W, Vigneshwaran R, et al. Identification of gastric cancer stem cells using the cell surface marker CD44. Stem Cells. 2009;27:1006–20.PubMedCrossRef

Wang B, Yu SC, Jiang JY, Porter GW, Zhao LT, Wang Z, et al. An inhibitor of arachidonate 5-lipoxygenase, Nordy, induces differentiation and inhibits self-renewal of glioma stem-like cells. Stem Cell Rev. 2011;7:458–70.PubMedCrossRef

Anders M, Vieth M, Rocken C, Ebert M, Pross M, Gretschel S, et al. Loss of the coxsackie and adenovirus receptor contributes to gastric cancer progression. Br J Cancer. 2009;100:352–9.PubMedCrossRef

Wang H, Liu Y, Li Z, Tuve S, Stone D, Kalyushniy O, et al. In vitro and in vivo properties of adenovirus vectors with increased affinity to CD46. J Virol. 2008;82:10567–79.PubMedCrossRef

He X, Liu J, Yang C, Su C, Zhou C, Zhang Q, et al. 5/35 fiber-modified conditionally replicative adenovirus armed with p53 shows increased tumor-suppressing capacity to breast cancer cells. Hum Gene Ther. 2011;22:283–92.PubMedCrossRef

10.

Chen W, Wu Y, Liu W, Wang G, Wang X, Yang Y, et al. Enhanced antitumor efficacy of a novel fiber chimeric oncolytic adenovirus expressing p53 on hepatocellular carcinoma. Cancer Lett. 2011;307:93–103.PubMedCrossRef

11.

Zhao Y, Li Y, Wang Q, Wang L, Yang H, Li M. Increased antitumor capability of fiber-modified adenoviral vector armed with TRAIL against bladder cancers. Mol Cell Biochem. 2011;353:93–9.PubMedCrossRef

12.

Chen L, Chen D, Gong M, Na M, Li L, Wu H, et al. Concomitant use of Ad5/35 chimeric oncolytic adenovirus with TRAIL gene and taxol produces synergistic cytotoxicity in gastric cancer cells. Cancer Lett. 2009;284:141–8.PubMedCrossRef

13.

Greig JA, Buckley SM, Waddington SN, Parker AL, Bhella D, Pink R, et al. Influence of coagulation factor x on in vitro and in vivo gene delivery by adenovirus (Ad) 5, Ad35, and chimeric Ad5/Ad35 vectors. Mol Ther. 2009;17:1683–91.PubMedCrossRef

14.

Zheng HC, Xu XY, Xia P, Yu M, Takahashi H, Takano Y. Involvement of inactive GSK3beta overexpression in tumorigenesis and progression of gastric carcinomas. Hum Pathol. 2010;41:1255–64.PubMedCrossRef

15.

Reya T, Clevers H. Wnt signalling in stem cells and cancer. Nature. 2005;434:843–50.PubMedCrossRef

16.

Liu X, Qian Q, Xu P, Wolf F, Zhang J, Zhang D, et al. A novel conditionally replicating “armed” adenovirus selectively targeting gastrointestinal tumors with aberrant Wnt signaling. Hum Gene Ther. 2011;22:427–37.PubMedCrossRef

17.

Jiang H, Xia J, Kang J, Ding Y, Wu W. Short hairpin RNA targeting beta-catenin suppresses cell proliferation and induces apoptosis in human gastric carcinoma cells. Scand J Gastroenterol. 2009;44:1452–62.PubMedCrossRef

18.

Oh H, Chun CH, Chun JS. Dickkopf-1 expression in chondrocytes inhibits experimental osteoarthritic cartilage destruction in mice. Arthr Rheum. 2012;64:2568–78.CrossRef

19.

Kuhnert F, Davis CR, Wang HT, Chu P, Lee M, Yuan J, et al. Essential requirement for Wnt signaling in proliferation of adult small intestine and colon revealed by adenoviral expression of Dickkopf-1. Proc Natl Acad Sci USA. 2004;101:266–71.PubMedCrossRef

20.

Cai C, Zhu X. The Wnt/beta-catenin pathway regulates self-renewal of cancer stem-like cells in human gastric cancer. Mol Med Rep. 2012;5:1191–6.PubMed

21.

Schepers A, Clevers H. Wnt signaling, stem cells, and cancer of the gastrointestinal tract. Cold Spring Harb Perspect Biol. 2012. doi:10.1101/cshperspect.a007989.

22.

Takagi H, Sasaki S, Suzuki H, Toyota M, Maruyama R, Nojima M, et al. Frequent epigenetic inactivation of SFRP genes in hepatocellular carcinoma. J Gastroenterol. 2008;43:378–89.PubMedCrossRef

23.

Jiang H, Gomez-Manzano C, Aoki H, Alonso MM, Kondo S, McCormick F, et al. Examination of the therapeutic potential of Delta-24-RGD in brain tumor stem cells: role of autophagic cell death. J Natl Cancer Inst. 2007;99:1410–4.PubMedCrossRef

24.

Barker N, Van Es JH, Kuipers J, Kujala P, Van Den Born M, Cozijnsen M, et al. Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature. 2007;449:1003–7.PubMedCrossRef

25.

Van Der Flier LG, Sabates-Bellver J, Oving I, Haegebarth A, De Palo M, Anti M, et al. The intestinal Wnt/TCF signature. Gastroenterology. 2007;132:628–32.PubMedCrossRef

26.

Benhamouche S, Decaens T, Godard C, Chambrey R, Rickman DS, Moinard C, et al. Apc tumor suppressor gene is the “zonation-keeper” of mouse liver. Dev Cell. 2006;10:759–70.PubMedCrossRef

27.

Hirata H, Hinoda Y, Nakajima K, Kawamoto K, Kikuno N, Ueno K, et al. Wnt antagonist DKK1 acts as a tumor suppressor gene that induces apoptosis and inhibits proliferation in human renal cell carcinoma. Int J Cancer. 2011;128:1793–803.PubMedCrossRef

28.

Lowy AM, Clements WM, Bishop J, Kong L, Bonney T, Sisco K, et al. beta-catenin/Wnt signaling regulates expression of the membrane type 3 matrix metalloproteinase in gastric cancer. Cancer Res. 2006;66:4734–41.PubMedCrossRef

29.

Hanaki H, Yamamoto H, Sakane H, Matsumoto S, Ohdan H, Sato A. An anti-Wnt5a antibody suppresses metastasis of gastric cancer cells in vivo by inhibiting receptor-mediated endocytosis. Mol Cancer Ther. 2012;11:298–307.PubMedCrossRef

30.

Deng YZ, Yao F, Li JJ, Mao ZF, Hu PT, Long LY, et al. RACK1 suppresses gastric tumorigenesis by stabilizing the beta-catenin destruction complex. Gastroenterology. 2012;142:812–23.PubMedCrossRef

31.

Clevers H, Nusse R. Wnt/beta-catenin signaling and disease. Cell. 2012;149:1192–205.PubMedCrossRef

32.

White BD, Chien AJ, Dawson DW. Dysregulation of Wnt/beta-catenin signaling in gastrointestinal cancers. Gastroenterology. 2012;142:219–32.PubMedCrossRef

Titel: Chimeric 5/35 adenovirus-mediated Dickkopf-1 overexpression suppressed tumorigenicity of CD44+ gastric cancer cells via attenuating Wnt signaling
verfasst von: Bin Wang
Jia Liu
Lei Na Ma
Hua Liang Xiao
Ya Zhou Wang
Yan Li
Zhe Wang
Linli Fan
Chunhui Lan
Min Yang
Lu Hu
Yanlin Wei
Xiu Wu Bian
Dongfeng Chen
Jun Wang
Publikationsdatum: 01.07.2013
Verlag: Springer Japan
Erschienen in: Journal of Gastroenterology / Ausgabe 7/2013
Print ISSN: 0944-1174
Elektronische ISSN: 1435-5922
DOI: https://doi.org/10.1007/s00535-012-0711-z

Leitlinien kompakt für die Innere Medizin

Mit medbee Pocketcards sicher entscheiden.

^{Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag}

Kostenlos registrieren

Neu im Fachgebiet Innere Medizin

24.04.2024 | DGIM 2024 | Kongressbericht | Nachrichten

Update Innere Medizin

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Springer Medizin

Chimeric 5/35 adenovirus-mediated Dickkopf-1 overexpression suppressed tumorigenicity of CD44⁺ gastric cancer cells via attenuating Wnt signaling

Abstract

Background

Methods

Results

Conclusions

Leitlinien kompakt für die Innere Medizin

Neu im Fachgebiet Innere Medizin

Metformin rückt in den Hintergrund

Myokarditis nach Infekt – richtig schwierig wird es bei Profisportlern

Thrombophiliescreening – Wenn, dann richtig und nur bei therapeutischer Konsequenz

Bei Senioren mit Prostatakarzinom auf Anämie achten!

Update Innere Medizin

Springer Medizin

Abstract

Background

Methods

Results

Conclusions

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 7/2013

Clinical effectiveness of bipolar radiofrequency ablation for small liver cancers

Clinical usefulness of repeated pancreatic juice cytology via endoscopic naso-pancreatic drainage tube in patients with pancreatic cancer

Characterization of polyethylene glycol-grafted polyethylenimine and superparamagnetic iron oxide nanoparticles (PEG-g-PEI-SPION) as an MRI-visible vector for siRNA delivery in gastric cancer in vitro and in vivo

A bioabsorbable polymer patch for the treatment of esophageal defect in a porcine model

Risk factors for the exacerbation of esophageal varices or portosystemic encephalopathy after sustained virological response with IFN therapy for HCV-related compensated cirrhosis

Cancer stem cells: the ‘heartbeat’ of gastric cancer

Leitlinien kompakt für die Innere Medizin

Neu im Fachgebiet Innere Medizin

Metformin rückt in den Hintergrund

Myokarditis nach Infekt – richtig schwierig wird es bei Profisportlern

Thrombophiliescreening – Wenn, dann richtig und nur bei therapeutischer Konsequenz

Bei Senioren mit Prostatakarzinom auf Anämie achten!

Update Innere Medizin