Establishment of hypoxia induction in an in vivo animal replacement model for experimental evaluation of pancreatic cancer Corrigendum in /10.3892/or.2023.8626

Bauer,Nathalie; Liu,Li; Aleksandrowicz,Ewa; Herr,Ingrid

doi:10.3892/or.2014.3196

Establishment of hypoxia induction in an in vivo animal replacement model for experimental evaluation of pancreatic cancer

Corrigendum in: /10.3892/or.2023.8626

Authors:
- Nathalie Bauer
- Li Liu
- Ewa Aleksandrowicz
- Ingrid Herr
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Affiliations: Molecular Oncosurgery, Department of General and Transplantation Surgery, University of Heidelberg and German Cancer Research Center (DKFZ), D-69120 Heidelberg, Germany
Published online on: May 16, 2014 https://doi.org/10.3892/or.2014.3196
Pages: 153-158

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Abstract

Transplantation of tumor xenografts to fertilized chicken eggs is a promising animal replacement method, which has successfully been used for xenotransplantation of pancreatic ductal adenocarcinoma (PDA) cells. PDA is characterized by a pronounced tumor hypoxia, which mediates aggressive growth, therapy resistance and cancer stem cell (CSC) features. For in vivo experimental evaluation of hypoxia-targeting therapeutic strategies, the xenografting of tumors to chicken eggs combined with the induction of hypoxia is necessary. However, the chicken embryos do not survive the conventional method of hypoxia induction by a gas mixture of 1% O2, 5% CO2, 94% N2, not even when hypoxia is applied for only 30 min. Therefore, we employed chemical induction of hypoxia by the hypoxia mimetic agent cobalt chloride (CoCl2). Whereas CoCl2 did not further increase tumor growth, it mediated the induction of carbonic anhydrase IX (CAIX) in the tumor xenografts and led to enhanced expression of the human CSC markers CD133, Sox2 and CD44. Side-effects in chicken embryos were not observed as evaluated by H&E staining of embryo-derived liver sections and the determination of the embryo weight. These results suggest the successful induction of hypoxia in chicken eggs and xenografted tumors by CoCl2. For therapeutic intervention and as a control, we treated the eggs with the plant-derived anti-inflammatory agent triptolide, which recently showed promising effects toward hypoxia-induced tumor progression in experimental PDA. Triptolide abolished tumor growth and the CoCl2-induced hypoxic effects, without inducing obvious side-effects. Collectively, our data present a new in vivo animal replacement method for the successful induction of tumor hypoxia in PDA.

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1	Liu L, Salnikov AV, Bauer N, Aleksandrowicz E, Labsch S, Nwaeburu C, Mattern J, Gladkich J, Schemmer P, Werner J and Herr I: Triptolide reverses hypoxia-induced EMT and stem-like features in pancreatic cancer by NF-κB downregulation. Int J Cancer. 134:2849–2503. 2014.PubMed/NCBI
2	Ribatti D, Nico B, Vacca A and Presta M: The gelatin sponge-chorioallantoic membrane assay. Nat Protoc. 1:85–91. 2006. View Article : Google Scholar : PubMed/NCBI
3	Schneiderhan W, Scheler M, Holzmann KH, Marx M, Gschwend JE, Bucholz M, Gress TM, Seufferlein T, Adler G and Oswald F: CD147 silencing inhibits lactate transport and reduces malignant potential of pancreatic cancer cells in in vivo and in vitro models. Gut. 58:1391–1398. 2009. View Article : Google Scholar : PubMed/NCBI
4	Janse EM and Jeurissen SH: Ontogeny and function of two non-lymphoid cell populations in the chicken embryo. Immunobiology. 182:472–481. 1991. View Article : Google Scholar : PubMed/NCBI
5	Brown JM and Giaccia AJ: The unique physiology of solid tumors: opportunities (and problems) for cancer therapy. Cancer Res. 58:1408–1416. 1998.PubMed/NCBI
6	Hoffmann AC, Mori R, Vallbohmer D, Brabender J, Klein E, Drebber U, Baldus SE, Cooc J, Azuma M, Metzger R, Hoelscher AH, Danenberg KD, Prenzel KL and Danenberg PV: High expression of HIF1α is a predictor of clinical outcome in patients with pancreatic ductal adenocarcinomas and correlated to PDGFA, VEGF, and bFGF. Neoplasia. 10:674–679. 2008.
7	Chang Q, Jurisica I, Do T and Hedley DW: Hypoxia predicts aggressive growth and spontaneous metastasis formation from orthotopically grown primary xenografts of human pancreatic cancer. Cancer Res. 71:3110–3120. 2011. View Article : Google Scholar
8	Ho VT and Bunn HF: Effects of transition metals on the expression of the erythropoietin gene: further evidence that the oxygen sensor is a heme protein. Biochem Biophys Res Commun. 223:175–180. 1996. View Article : Google Scholar : PubMed/NCBI
9	Gray MJ, Zhang J, Ellis LM, Semenza GL, Evans DB, Watowich SS and Gallick GE: HIF-1α, STAT3, CBP/p300 and Ref-1/APE are components of a transcriptional complex that regulates Src-dependent hypoxia-induced expression of VEGF in pancreatic and prostate carcinomas. Oncogene. 24:3110–3120. 2005.
10	Brinker AM, Ma J, Lipsky PE and Raskin I: Medicinal chemistry and pharmacology of genus Tripterygium (Celastraceae). Phytochemistry. 68:732–766. 2007. View Article : Google Scholar : PubMed/NCBI
11	Balke M, Neumann A, Szuhai K, Agelopoulos K, August C, Gosheger G, Hogendoorn PC, Athanasou N, Buerger H and Hagedorn M: A short-term in vivo model for giant cell tumor of bone. BMC Cancer. 11:2412011. View Article : Google Scholar : PubMed/NCBI
12	Moldenhauer G, Momburg F, Möller P, Schwartz R and Hämmerling GJ: Epithelium-specific surface glycoprotein of Mr 34,000 is a widely distributed human carcinoma marker. Br J Cancer. 56:714–721. 1987. View Article : Google Scholar
13	Weber E, Lehmann HP, Beck-Sickinger AG, Wawrzynczak EJ, Waibel R, Folkers G and Stahel RA: Antibodies to the protein core of the small cell lung cancer workshop antigen cluster-w4 and to the leucocyte workshop antigen CD24 recognize the same short protein sequence leucine-alanine-proline. Clin Exp Immunol. 93:279–285. 1993. View Article : Google Scholar
14	Rausch V, Liu L, Apel A, Rettig T, Gladkich J, Labsch S, Kallifatidis G, Kaczorowski A, Groth A, Gross W, Gebhard MM, Schemmer P, Werner J, Salnikov AV, Zentgraf H, Büchler MW and Herr I: Autophagy mediates survival of pancreatic tumour-initiating cells in a hypoxic microenvironment. J Pathol. 227:325–335. 2012. View Article : Google Scholar : PubMed/NCBI
15	Kallifatidis G, Rausch V, Baumann B, Apel A, Beckermann BM, Groth A, Mattern J, Li Z, Kolb A, Moldenhauer G, Altevogt P, Wirth T, Werner J, Schemmer P, Büchler MW, Salnikov A and Herr I: Sulforaphane targets pancreatic tumour-initiating cells by NF-κB-induced antiapoptotic signalling. Gut. 58:949–963. 2009.PubMed/NCBI
16	Salnikov AV, Liu L, Platen M, Gladkich J, Salnikova O, Ryschich E, Mattern J, Moldenhauer G, Werner J, Schemmer P, Büchler MW and Herr I: Hypoxia induces EMT in low and highly aggressive pancreatic tumor cells but only cells with cancer stem cell characteristics acquire pronounced migratory potential. PLoS One. 7:e463912012. View Article : Google Scholar
17	Lester RD, Jo M, Montel V, Takimoto S and Gonias SL: uPAR induces epithelial-mesenchymal transition in hypoxic breast cancer cells. J Cell Biol. 178:425–436. 2007. View Article : Google Scholar : PubMed/NCBI