nach oben

Erschienen in:

01.05.2007 | Research Paper

Establishment of a novel orthotopic xenograft model of human gallbladder carcinoma

verfasst von: Jan-Hendrik Egberts, Bodo Schniewind, Clemens Schafmayer, Marie-Luise Kruse, Bence Sipos, Fred Fändrich, Holger Kalthoff, Jürgen Tepel

Erschienen in: Clinical & Experimental Metastasis | Ausgabe 3/2007

Einloggen, um Zugang zu erhalten

Abstract

Objective

Gallbladder cancer is characterized by high morbidity and mortality. An appropriate human xenograft animal model could serve as a research tool to investigate new therapeutic strategies.

Summary background data

To date, the few reports describing a xenograft animal model showed significant limitations. We improved a murine orthotopic human xenotransplantation model by implanting human gallbladder carcinoma cells directly into the lumen of the gallbladder.

Methods

Mz-ChA-1 cells were orthotopically injected into the gallbladder of Severe Combined Immune Deficiency (SCID) beige mice inducing the growth of solid tumors. The natural course of the disease, tumor growth, and metastases were analyzed. The cytotoxic drug gemcitabine was tested in vitro and in vitro.

Results

All animals revealed solid tumors in the inoculated area with liver infiltration. The median tumor volume in the untreated group was significantly higher than in the gemcitabine-treated group. Immunohistochemical staining revealed expression of human cytokeratin 7 and cytokeratin 8. To analyze tumor cell proliferation, the tumors were stained for the antigen Ki-67, and labeling indices were calculated for both groups. Animals receiving gemcitabine treatment showed significantly lower mean labeling indices. In vitro investigation revealed a significant reduction of DNA synthesis. DNA fragmentation, as a measure of apoptosis, was elevated by roughly 20% within 24 h of treatment. With this, we successfully established an orthotopic xenotransplant animal model and investigated the in vitro and in vivo effects of gemcitabine in human xenografted Mz-ChA-1 gallbladder adenocarcinoma.

Conclusion

This model resembles the clinical situation as closely as possible and offers a relevant option for the preclinical testing of new therapeutic strategies.

Olnes MJ, Erlich R (2004) A review and update on cholangiocarcinoma. Oncology 66(3):167–179PubMedCrossRef

Thongprasert S (2005) The role of chemotherapy in cholangiocarcinoma. Ann Oncol 16(suppl 2):ii93–ii96PubMedCrossRef

Khan SA, Thomas HC, Davidson BR, Taylor-Robinson SD (2005) Cholangiocarcinoma. Lancet 366(9493):1303–1314PubMedCrossRef

Todoroki T, Ohara K, Kawamoto T, Koike N, Yoshida S, Kashiwagi H, Otsuka M et al (2000) Benefits of adjuvant radiotherapy after radical resection of locally advanced main hepatic duct carcinoma. Int J Radiat Oncol Biol Phys 46(3):581–587PubMedCrossRef

Hejna M, Pruckmayer M, Raderer M (1998) The role of chemotherapy and radiation in the management of biliary cancer: a review of the literature. Eur J Cancer 34(7):977–986PubMedCrossRef

Knuth A, Gabbert H, Dippold W, Klein O, Sachsse W, Bitter-Suermann D, Prellwitz W et al (1985) Biliary adenocarcinoma: characterisation of three new human tumor cell lines. J Hepatol 1(6):579–596PubMedCrossRef

Ku JL, Yoon KA, Kim IJ, Kim WH, Jang JY, Suh KS, Kim SW et al (2002) Establishment and characterisation of six human biliary tract cancer cell lines. Br J Cancer 87(2):187–193PubMedCrossRef

Iemura A, Maruiwa M, Yano H, Kojiro M (1992) A new human cholangiocellular carcinoma cell line (KMC-1). J Hepatol 15(3):288–298PubMedCrossRef

Emura F, Kamma H, Ghosh M, Koike N, Kawamoto T, Saijo K, Ohno T et al (2003) Establishment and characterization of novel xenograft models of human biliary tract carcinomas. Int J Oncol 23(5):1293–1300PubMed

10.

Kamenz T, Caca K, Bluthner T, Tannapfel A, Mossner J, Wiedmann M (2006) Expression of c-kit receptor in human cholangiocarcinoma and in vivo treatment with imatinib mesilate in chimeric mice. World J Gastroenterol 12(10):1583–1590PubMed

11.

Gohongi T, Todoroki T, Fukumura D, Jain RK (2004) Influence of the site of human gallbladder xenograft (Mz-ChA-1) on angiogenesis at the distant site. Oncol Rep 11(4):803–807PubMed

12.

Horiuchi H, Kawamata H, Fujimori T, Kuroda Y (2003) A MEK inhibitor (U0126) prolongs survival in nude mice bearing human gallbladder cancer cells with K-ras mutation: analysis in a novel orthotopic inoculation model. Int J Oncol 23(4):957–963PubMed

13.

Park JS, Oh SY, Kim SH, Kwon HC, Kim JS, Jin-Kim H, Kim YH (2005) Single-agent gemcitabine in the treatment of advanced biliary tract cancers: a phase II study. Jpn J Clin Oncol 35(2):68–73PubMedCrossRef

14.

Gebbia V, Giuliani F, Maiello E, Colucci G, Verderame F, Borsellino N, Mauceri G et al (2001) Treatment of inoperable and/or metastatic biliary tree carcinomas with single-agent gemcitabine or in combination with levofolinic acid and infusional fluorouracil: results of a multicenter phase II study. J Clin Oncol 19(20):4089–4091PubMed

15.

Tsavaris N, Kosmas C, Gouveris P, Gennatas K, Polyzos A, Mouratidou D, Tsipras H et al (2004) Weekly gemcitabine for the treatment of biliary tract and gallbladder cancer. Invest New Drugs 22(2):193–198PubMedCrossRef

16.

Penz M, Kornek GV, Raderer M, Ulrich-Pur H, Fiebiger W, Lenauer A, Depisch D et al (2001) Phase II trial of two-weekly gemcitabine in patients with advanced biliary tract cancer. Ann Oncol 12(2):183–186PubMedCrossRef

17.

Tomayko MM, Reynolds CP (1989) Determination of subcutaneous tumor size in athymic (nude) mice. Cancer Chemother Pharmacol 24(3):148–154PubMedCrossRef

18.

West J, Wood H, Logan RF, Quinn M, Aithal GP (2006) Trends in the incidence of primary liver and biliary tract cancers in England and Wales 1971–2001. Br J Cancer 94(11):1751–1758PubMedCrossRef

19.

Khan SA, Taylor-Robinson SD, Toledano MB, Beck A, Elliott P, Thomas HC (2002) Changing international trends in mortality rates for liver, biliary and pancreatic tumours. J Hepatol 37(6):806–813PubMedCrossRef

20.

Patel T (2002) Worldwide trends in mortality from biliary tract malignancies. BMC Cancer 2:10PubMedCrossRef

21.

Alberts SR, Al-Khatib H, Mahoney MR, Burgart L, Cera PJ, Flynn PJ, Finch TR et al (2005) Gemcitabine, 5-fluorouracil, and leucovorin in advanced biliary tract and gallbladder carcinoma: a North Central Cancer Treatment Group phase II trial. Cancer 103(1):111–118PubMedCrossRef

22.

Radaeva S, Ferreira-Gonzalez A, Sirica AE (1999) Overexpression of C-NEU and C-MET during rat liver cholangiocarcinogenesis: a link between biliary intestinal metaplasia and mucin-producing cholangiocarcinoma. Hepatology 29(5):1453–1462PubMedCrossRef

23.

Elmore LW, Sirica AE (1993) “Intestinal-type” of adenocarcinoma preferentially induced in right/caudate liver lobes of rats treated with furan. Cancer Res 53(2):254–259PubMed

24.

Sirica AE (1996) Biliary proliferation and adaptation in furan-induced rat liver injury and carcinogenesis. Toxicol Pathol 24(1):90–99PubMedCrossRef

25.

Thamavit W, Pairojkul C, Tiwawech D, Itoh M, Shirai T, Ito N (1993) Promotion of cholangiocarcinogenesis in the hamster liver by bile duct ligation after dimethylnitrosamine initiation. Carcinogenesis 14(11):2415–2417PubMedCrossRef

26.

Iki K, Tsujiuchi T, Majima T, Sakitani H, Tsutsumi M, Takahama M, Yoshimoto M et al (1998) Increased telomerase activity in intrahepatic cholangiocellular carcinomas induced by N-nitrosobis(2-oxopropyl)amine in hamsters. Cancer Lett 131(2):185–190PubMedCrossRef

27.

Tengchaisri T, Prempracha N, Thamavit W, Boonpucknavig S, Sriurairatana S, Sirisinha S (1995) Establishment and characterization of cell lines from liver fluke-associated cholangiocarcinoma induced in a hamster model. Southeast Asian J Trop Med Public Health 26(2):231–239PubMed

28.

Tesana S, Takahashi Y, Sithithaworn P, Ando K, Sakakura T, Yutanawiboonchai W, Pairojkul C et al (2000) Ultrastructural and immunohistochemical analysis of cholangiocarcinoma in immunized Syrian golden hamsters infected with Opisthorchis viverrini and administered with dimethylnitrosamine. Parasitol Int 49(3):239–251PubMedCrossRef

29.

Imray CH, Newbold KM, Davis A, Lavelle-Jones M, Neoptolemos JP (1992) Induction of cholangiocarcinoma in the Golden Syrian hamster using methylazoxymethyl acetate. Eur J Surg Oncol 18(4):373–378PubMed

30.

Kiguchi K, Carbajal S, Chan K, Beltran L, Ruffino L, Shen J, Matsumoto T et al (2001) Constitutive expression of ErbB-2 in gallbladder epithelium results in development of adenocarcinoma. Cancer Res 61(19):6971–6976PubMed

31.

Yamaguchi N, Morioka H, Ohkura H, Hirohashi S, Kawai K (1985) Establishment and characterization of the human cholangiocarcinoma cell line HChol-Y1 in a serum-free, chemically defined medium. J Natl Cancer Inst 75(1):29–35PubMed

32.

Shimizu Y, Demetris AJ, Gollin SM, Storto PD, Bedford HM, Altarac S, Iwatsuki S et al (1992) Two new human cholangiocarcinoma cell lines and their cytogenetics and responses to growth factors, hormones, cytokines or immunologic effector cells. Int J Cancer 52(2):252–260PubMedCrossRef

33.

Tsubono M, Nio Y, Tseng CC, Kawabata K, Masai Y, Hayashi H, Fukumoto M et al (1992) Experimental chemotherapy for xenograft cell lines of human bile duct and gall bladder cancers in nude mice. J Surg Oncol 51(4):274–280PubMedCrossRef

34.

Wiedmann M, Feisthammel J, Bluthner T, Tannapfel A, Kamenz T, Kluge A, Mossner J et al (2006) Novel targeted approaches to treating biliary tract cancer: the dual epidermal growth factor receptor and ErbB-2 tyrosine kinase inhibitor NVP-AEE788 is more efficient than the epidermal growth factor receptor inhibitors gefitinib and erlotinib. Anticancer Drugs 17(7):783–795PubMedCrossRef

35.

Gohongi T, Fukumura D, Boucher Y, Yun CO, Soff GA, Compton C, Todoroki T et al (1999) Tumor–host interactions in the gallbladder suppress distal angiogenesis and tumor growth: involvement of transforming growth factor beta1. Nat Med 5(10):1203–1208PubMedCrossRef

36.

Fava G, Marucci L, Glaser S, Francis H, De Morrow S, Benedetti A, Alvaro D et al (2005) Gamma-aminobutyric acid inhibits cholangiocarcinoma growth by cyclic AMP-dependent regulation of the protein kinase A/extracellular signal-regulated kinase 1/2 pathway. Cancer Res 65(24):11437–11446PubMedCrossRef

37.

Date K, Matsumoto K, Kuba K, Shimura H, Tanaka M, Nakamura T (1998) Inhibition of tumor growth and invasion by a four-kringle antagonist (HGF/NK4) for hepatocyte growth factor. Oncogene 17(23):3045–3054PubMedCrossRef

38.

Nishime C, Ohnishi Y, Suemizu H, Tamaoki N, Suematsu M, Oida Y, Yamazaki H et al (2006) Gallbladder small cell carcinoma Xenograft established by serial transplantation in nude mice. Anticancer Res 26(1A):79–83PubMed

39.

Doctor RB, Matzakos T, McWilliams R, Johnson S, Feranchak AP, Fitz JG (2005) Purinergic regulation of cholangiocyte secretion: identification of a novel role for P2X receptors. Am J Physiol Gastrointest Liver Physiol 288(4):G779–G786PubMedCrossRef

40.

Marienfeld C, Tadlock L, Yamagiwa Y, Patel T (2003) Inhibition of cholangiocarcinoma growth by tannic acid. Hepatology 37(5):1097–1104PubMedCrossRef

41.

Roman RM, Bodily KO, Wang Y, Raymond JR, Fitz JG (1998) Activation of protein kinase Calpha couples cell volume to membrane Cl-permeability in HTC hepatoma and Mz-ChA-1 cholangiocarcinoma cells. Hepatology 28(4):1073–1080PubMedCrossRef

42.

Kwiatkowski AP, McGill JM (1995) Human biliary epithelial cell line Mz-ChA-1 expresses new isoforms of calmodulin-dependent protein kinase II. Gastroenterology 109(4):1316–1323PubMedCrossRef

Titel: Establishment of a novel orthotopic xenograft model of human gallbladder carcinoma
verfasst von: Jan-Hendrik Egberts
Bodo Schniewind
Clemens Schafmayer
Marie-Luise Kruse
Bence Sipos
Fred Fändrich
Holger Kalthoff
Jürgen Tepel
Publikationsdatum: 01.05.2007
Verlag: Kluwer Academic Publishers
Erschienen in: Clinical & Experimental Metastasis / Ausgabe 3/2007
Print ISSN: 0262-0898
Elektronische ISSN: 1573-7276
DOI: https://doi.org/10.1007/s10585-007-9058-x

Neu im Fachgebiet Onkologie

25.04.2024 | Nierenkarzinom | Nachrichten

Springer Medizin

Establishment of a novel orthotopic xenograft model of human gallbladder carcinoma

Abstract

Objective

Summary background data

Methods

Results

Conclusion

Neu im Fachgebiet Onkologie

Adjuvante Immuntherapie verlängert Leben bei RCC

Alectinib verbessert krankheitsfreies Überleben bei ALK-positivem NSCLC

Bei Senioren mit Prostatakarzinom auf Anämie achten!

ICI-Therapie in der Schwangerschaft wird gut toleriert

Update Onkologie

Springer Medizin

Abstract

Objective

Summary background data

Methods

Results

Conclusion

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

Weitere Artikel der Ausgabe 3/2007

A novel study investigating the therapeutic outcome of patients with lytic, mixed and sclerotic bone metastases treated with combined radiotherapy and ibandronate

Novel hyperthermia for metastatic bone tumors with magnetic materials by generating an alternating electromagnetic field

CA9 gene expression in conventional renal cell carcinoma: a potential marker for prediction of early metastasis after nephrectomy

Comparative analysis of intraperitoneal minimal free cancer cells between colorectal and gastric cancer patients using quantitative RT-PCR: possible reason for rare peritoneal recurrence in colorectal cancer

Src kinase promotes adhesion-independent activation of FAK and enhances cellular migration in tamoxifen-resistant breast cancer cells

Carcinoembryonic antigen-stimulated THP-1 macrophages activate endothelial cells and increase cell–cell adhesion of colorectal cancer cells

Neu im Fachgebiet Onkologie

Adjuvante Immuntherapie verlängert Leben bei RCC

Alectinib verbessert krankheitsfreies Überleben bei ALK-positivem NSCLC

Bei Senioren mit Prostatakarzinom auf Anämie achten!

ICI-Therapie in der Schwangerschaft wird gut toleriert

Update Onkologie