Establishment of two ovarian cancer orthotopic xenograft mouse models for in vivo imaging: A comparative study

Guo,Jing; Cai,Jing; Zhang,Yunxia; Zhu,Yapei; Yang,Ping; Wang,Zehua

doi:10.3892/ijo.2017.4115

Establishment of two ovarian cancer orthotopic xenograft mouse models for in vivo imaging: A comparative study

Authors:
- Jing Guo
- Jing Cai
- Yunxia Zhang
- Yapei Zhu
- Ping Yang
- Zehua Wang
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Affiliations: Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, P.R. China, Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Beijing 100730, P.R. China, Department of Obstetrics and Gynecology, First Affiliated Hospital, School of Medicine, Shihezi University, Shihezi, Xinjiang 832008, P.R. China
Published online on: September 4, 2017 https://doi.org/10.3892/ijo.2017.4115
Pages: 1199-1208

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Abstract

Orthotopic tumor animal models are optimal for preclinical research of novel therapeutic interventions. The aim of the present study was to compare two types of ovarian cancer orthotopic xenograft (OCOX) mouse models, i.e. cellular orthotopic injection (COI) and surgical orthotopic implantation (SOI), regarding xenograft formation rate, in vivo imaging, tumor growth and metastasis, and tumor microenvironment. The tumor formation and progression were monitored by bioluminescent in vivo imaging. Cell proliferation and migration abilities were detected by EdU and scratch assays, respectively. Expression of α-SMA, CD34, MMP2, MMP9, vimentin, E-cadherin and Ki67 in tumor samples were detected by immunohistochemistry. As a result, we successfully established COI- and SOI-OCOX mouse models using ovarian cancer cell lines ES2 and SKOV3. The tumor formation rate in the COI and SOI models were 87.5 and 100%, respectively. Suspected tumor cell leakage occurred in 37.5% of the COI models. The SOI xenografts grew faster, held larger primary tumors, and were more metastatic than the COI xenografts. The migration and proliferation properties of the cells that generated SOI xenografts were significantly starker than those deriving COI xenografts in vitro. The tumor cells in SOI xenografts exhibited a mesenchymal phenotype and proliferated more actively than those in the COI xenografts. Additionally, compared with the COI tumors, the SOI tumors contained more cancer associated fibroblasts, matrix metallopeptidase 2 and 9. In conclusion, SOI is a feasible and reliable technique to establish OCOX mouse models mimicking the clinical process of ovarian cancer growth and metastasis, although SOI is more technically difficult and time-consuming than COI.

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1	Siegel RL, Miller KD and Jemal A: Cancer statistics, 2016. CA Cancer J Clin. 66:7–30. 2016. View Article : Google Scholar : PubMed/NCBI
2	Kerbel RS: A decade of experience in developing preclinical models of advanced- or early-stage spontaneous metastasis to study antiangiogenic drugs, metronomic chemotherapy, and the tumor microenvironment. Cancer J. 21:274–283. 2015. View Article : Google Scholar : PubMed/NCBI
3	Singh M, Lima A, Molina R, Hamilton P, Clermont AC, Devasthali V, Thompson JD, Cheng JH, Bou Reslan H, Ho CC, et al: Assessing therapeutic responses in Kras mutant cancers using genetically engineered mouse models. Nat Biotechnol. 28:585–593. 2010. View Article : Google Scholar : PubMed/NCBI
4	Guerin E, Man S, Xu P and Kerbel RS: A model of postsurgical advanced metastatic breast cancer more accurately replicates the clinical efficacy of antiangiogenic drugs. Cancer Res. 73:2743–2748. 2013. View Article : Google Scholar : PubMed/NCBI
5	Bogden AE, Cobb WR, Lepage DJ, Haskell PM, Gulkin TA, Ward A, Kelton DE and Esber HJ: Chemotherapy responsiveness of human tumors as first transplant generation xenografts in the normal mouse: Six-day subrenal capsule assay. Cancer. 48:10–20. 1981. View Article : Google Scholar : PubMed/NCBI
6	Lee CH, Xue H, Sutcliffe M, Gout PW, Huntsman DG, Miller DM, Gilks CB and Wang YZ: Establishment of subrenal capsule xenografts of primary human ovarian tumors in SCID mice: Potential models. Gynecol Oncol. 96:48–55. 2005. View Article : Google Scholar
7	Céspedes MV, Casanova I, Parreño M and Mangues R: Mouse models in oncogenesis and cancer therapy. Clin Transl Oncol. 8:318–329. 2006. View Article : Google Scholar : PubMed/NCBI
8	Francia G, Cruz-Munoz W, Man S, Xu P and Kerbel RS: Mouse models of advanced spontaneous metastasis for experimental therapeutics. Nat Rev Cancer. 11:135–141. 2011. View Article : Google Scholar : PubMed/NCBI
9	Bibby MC: Orthotopic models of cancer for preclinical drug evaluation: Advantages and disadvantages. Eur J Cancer. 40:852–857. 2004. View Article : Google Scholar : PubMed/NCBI
10	Fu X and Hoffman RM: Human ovarian carcinoma metastatic models constructed in nude mice by orthotopic transplantation of histologically-intact patient specimens. Anticancer Res. 13:283–286. 1993.PubMed/NCBI
11	Sharpless NE and Depinho RA: The mighty mouse: Genetically engineered mouse models in cancer drug development. Nat Rev Drug Discov. 5:741–754. 2006. View Article : Google Scholar : PubMed/NCBI
12	Howell VM: Genetically engineered mouse models for epithelial ovarian cancer: Are we there yet? Semin Cell Dev Biol. 27:106–117. 2014. View Article : Google Scholar : PubMed/NCBI
13	Kiguchi K, Kubota T, Aoki D, Udagawa Y, Yamanouchi S, Saga M, Amemiya A, Sun FX, Nozawa S, Moossa AR, et al: A patient-like orthotopic implantation nude mouse model of highly metastatic human ovarian cancer. Clin Exp Metastasis. 16:751–756. 1998. View Article : Google Scholar
14	Tamada Y, Aoki D, Nozawa S and Irimura T: Model for paraaortic lymph node metastasis produced by orthotopic implantation of ovarian carcinoma cells in athymic nude mice. Eur J Cancer. 40:158–163. 2004. View Article : Google Scholar
15	Fu XY, Theodorescu D, Kerbel RS and Hoffman RM: Extensive multi-organ metastasis following orthotopic onplantation of histologically-intact human bladder carcinoma tissue in nude mice. Int J Cancer. 49:938–939. 1991. View Article : Google Scholar : PubMed/NCBI
16	Wang X, Fu X and Hoffman RM: A patient-like metastasizing model of human lung adenocarcinoma constructed via thoracotomy in nude mice. Anticancer Res. 12:1399–1401. 1992.PubMed/NCBI
17	Wang X, Fu X, Kubota T and Hoffman RM: A new patient-like metastatic model of human small-cell lung cancer constructed orthotopically with intact tissue via thoracotomy in nude mice. Anticancer Res. 12:1403–1406. 1992.PubMed/NCBI
18	An Z, Jiang P, Wang X, Moossa AR and Hoffman RM: Development of a high metastatic orthotopic model of human renal cell carcinoma in nude mice: Benefits of fragment implantation compared to cell-suspension injection. Clin Exp Metastasis. 17:265–270. 1999. View Article : Google Scholar : PubMed/NCBI
19	Morioka CY, Saito S, Ohzawa K and Watanabe A: Homologous orthotopic implantation models of pancreatic ductal cancer in Syrian golden hamsters: Which is better for metastasis research - cell implantation or tissue implantation? Pancreas. 20:152–157. 2000. View Article : Google Scholar : PubMed/NCBI
20	Yi C, Zhang L, Zhang F, Li L, Ling S, Wang X, Liu X and Liang W: Methodologies for the establishment of an orthotopic transplantation model of ovarian cancer in mice. Front Med. 8:101–105. 2014. View Article : Google Scholar : PubMed/NCBI
21	Tommelein J, Verset L, Boterberg T, Demetter P, Bracke M and De Wever O: Cancer-associated fibroblasts connect metastasis-promoting communication in colorectal cancer. Front Oncol. 5:632015. View Article : Google Scholar : PubMed/NCBI
22	Uzzan B, Nicolas P, Cucherat M and Perret GY: Microvessel density as a prognostic factor in women with breast cancer: A systematic review of the literature and meta-analysis. Cancer Res. 64:2941–2955. 2004. View Article : Google Scholar : PubMed/NCBI
23	Coussens LM, Fingleton B and Matrisian LM: Matrix metalloproteinase inhibitors and cancer: Trials and tribulations. Science. 295:2387–2392. 2002. View Article : Google Scholar : PubMed/NCBI
24	Micalizzi DS, Farabaugh SM and Ford HL: Epithelial-mesenchymal transition in cancer: Parallels between normal development and tumor progression. J Mammary Gland Biol Neoplasia. 15:117–134. 2010. View Article : Google Scholar : PubMed/NCBI
25	Xu B, Jin Q, Zeng J, Yu T, Chen Y, Li S, Gong D, He L, Tan X, Yang L, et al: Combined tumor- and neovascular-'dual targeting' gene/chemotherapy suppresses tumor growth and angiogenesis. ACS Appl Mater Interfaces. 8:25753–25769. 2016. View Article : Google Scholar : PubMed/NCBI
26	Zhang Y, Tang H, Cai J, Zhang T, Guo J, Feng D and Wang Z: Ovarian cancer-associated fibroblasts contribute to epithelial ovarian carcinoma metastasis by promoting angiogenesis, lymphangiogenesis and tumor cell invasion. Cancer Lett. 303:47–55. 2011. View Article : Google Scholar : PubMed/NCBI
27	Pei J, Fu W, Yang L, Zhang Z and Liu Y: Oxidative stress is involved in the pathogenesis of Keshan disease (an endemic dilated cardiomyopathy) in China. Oxid Med Cell Longev. 2013:4742032013. View Article : Google Scholar : PubMed/NCBI
28	Zhu Y, Cai L, Guo J, Chen N, Yi X, Zhao Y, Cai J and Wang Z: Depletion of Dicer promotes epithelial ovarian cancer progression by elevating PDIA3 expression. Tumour Biol. 37:14009–14023. 2016. View Article : Google Scholar : PubMed/NCBI
29	Torng PL, Mao TL, Chan WY, Huang SC and Lin CT: Prognostic significance of stromal metalloproteinase-2 in ovarian adenocarcinoma and its relation to carcinoma progression. Gynecol Oncol. 92:559–567. 2004. View Article : Google Scholar : PubMed/NCBI
30	Hassona Y, Cirillo N, Heesom K, Parkinson EK and Prime SS: Senescent cancer-associated fibroblasts secrete active MMP-2 that promotes keratinocyte dis-cohesion and invasion. Br J Cancer. 111:1230–1237. 2014. View Article : Google Scholar : PubMed/NCBI
31	Huang S, Van Arsdall M, Tedjarati S, McCarty M, Wu W, Langley R and Fidler IJ: Contributions of stromal metalloproteinase-9 to angiogenesis and growth of human ovarian carcinoma in mice. J Natl Cancer Inst. 94:1134–1142. 2002. View Article : Google Scholar : PubMed/NCBI
32	Yi XF, Yuan ST, Lu LJ, Ding J and Feng YJ: A clinically relevant orthotopic implantation nude mouse model of human epithelial ovarian cancer - based on consecutive observation. Int J Gynecol Cancer. 15:850–855. 2005. View Article : Google Scholar : PubMed/NCBI
33	Xu X, Ayub B, Liu Z, Serna VA, Qiang W, Liu Y, Hernando E, Zabludoff S, Kurita T, Kong B, et al: Anti-miR182 reduces ovarian cancer burden, invasion, and metastasis: An in vivo study in orthotopic xenografts of nude mice. Mol Cancer Ther. 13:1729–1739. 2014. View Article : Google Scholar : PubMed/NCBI
34	Nieman KM, Romero IL, Van Houten B and Lengyel E: Adipose tissue and adipocytes support tumorigenesis and metastasis. Biochim Biophys Acta. 1831:1533–1541. 2013. View Article : Google Scholar : PubMed/NCBI
35	Lungchukiet P, Sun Y, Kasiappan R, Quarni W, Nicosia SV, Zhang X and Bai W: Suppression of epithelial ovarian cancer invasion into the omentum by 1α,25-dihydroxyvitamin D3 and its receptor. J Steroid Biochem Mol Biol. 148:138–147. 2015. View Article : Google Scholar