A patient-derived xenograft mouse model generated from primary cultured cells recapitulates patient tumors phenotypically and genetically
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Preclinical trials of cancer therapeutics require both in vitro and in vivo evaluations. Recently, a patient-derived xenograft model in immunodeficient mice has been reported as a valuable in vivo evaluation system. In our current study, we aimed to establish a more efficient and accurate system for preclinical trials by generating primary cancer cells from patients and performing xenograft transfers of these cells into mice.
Human lung cancer specimens (n = 4) obtained from chemo-naive patients were cultured in bronchiolar epithelial basal medium supplemented with growth factors, followed by inoculation into non-obese diabetic/severe combined immunodeficient mice. The generated tumors in the mice were validated phenotypically and genetically using the original specimen and primary cancer cells.
Immunohistochemical analysis of marker proteins, including cytokeratin 7, cytokeratin 20, epidermal growth factor receptor, thyroid transcription factor-1, CD56, chromogranin, and synaptophysin, demonstrated that the xenograft tumors were originated from the patient tumors. Moreover, mutation profiling using the OncoMap System, which analyzes mutations at 440 sites in 41 tumor-related genes, showed the same patterns in both the patient and xenograft tumors.
These results indicate that our animal system is suitable for the amplification of patient tumors and will therefore be beneficial for both in vivo and in vitro assessments and preclinical trials of chemotherapeutics. This has the potential to provide a very effective tool for future personalized therapy and for conducting translational lung cancer research.
KeywordsPatient-derived primary cancer cells Xenograft model Lung cancer OncoMap
This study was supported by a grant of the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (A062254 and HI10C2014), and by the Leading Foreign Research Institute Recruitment Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning (MSIP) (2011-0030105).
Conflict of interest
- Bertolini G, Roz L, Perego P, Tortoreto M, Fontanella E, Gatti L, Pratesi G, Fabbri A, Andriani F, Tinelli S, Roz E, Caserini R, Lo Vullo S, Camerini T, Mariani L, Delia D, Calabro E, Pastorino U, Sozzi G (2009) Highly tumorigenic lung cancer CD133+ cells display stem-like features and are spared by cisplatin treatment. Proc Natl Acad Sci USA 106:16281–16286PubMedCrossRefGoogle Scholar
- Daniel VC, Marchionni L, Hierman JS, Rhodes JT, Devereux WL, Rudin CM, Yung R, Parmigiani G, Dorsch M, Peacock CD, Watkins DN (2009) A primary xenograft model of small-cell lung cancer reveals irreversible changes in gene expression imposed by culture in vitro. Cancer Res 69:3364–3373PubMedCrossRefGoogle Scholar
- Dong X, Guan J, English JC, Flint J, Yee J, Evans K, Murray N, Macaulay C, Ng RT, Gout PW, Lam WL, Laskin J, Ling V, Lam S, Wang Y (2010) Patient-derived first generation xenografts of non-small cell lung cancers: promising tools for predicting drug responses for personalized chemotherapy. Clin Cancer Res 16:1442–1451PubMedCrossRefGoogle Scholar
- Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ (2009) Cancer statistics, 2009 CA: a cancer journal for clinicians 59: 225–249Google Scholar
- John T, Kohler D, Pintilie M, Yanagawa N, Pham NA, Li M, Panchal D, Hui F, Meng F, Shepherd FA, Tsao MS (2011) The ability to form primary tumor xenografts is predictive of increased risk of disease recurrence in early-stage non-small cell lung cancer. Clin Cancer Res 17:134–141PubMedCrossRefGoogle Scholar
- John T, Yanagawa N, Kohler D, Craddock KJ, Bandarchi-Chamkhaleh B, Pintilie M, Sykes J, To C, Li M, Panchal D, Chen W, Shepherd FA, Tsao MS (2012) Characterization of lymphomas developing in immunodeficient mice implanted with primary human non-small cell lung cancer. J Thorac Oncol 7:1101–1108PubMedCrossRefGoogle Scholar
- Julien S, Merino-Trigo A, Lacroix L, Pocard M, Goere D, Mariani P, Landron S, Bigot L, Nemati F, Cuilliere-Dartigues P, Weiswald LB, Lantuas D, Morgand L, Pham E, Gonin P, Dangles-Marie V, Job B, Dessen P, Bruno A, Pierre A, De The H, Soliman H, Nunes M, Lardier G, Calvet L, Demers B, Prevost G, Vrignaud P, Roman-Roman S, Duchamp O, Berthet C (2012) Characterization of a large panel of patient-derived tumor xenografts representing the clinical heterogeneity of human colorectal cancer. Clin Cancer Res : an official journal of the American Association for Cancer ResearchGoogle Scholar
- MacConaill LE, Campbell CD, Kehoe SM, Bass AJ, Hatton C, Niu L, Davis M, Yao K, Hanna M, Mondal C, Luongo L, Emery CM, Baker AC, Philips J, Goff DJ, Fiorentino M, Rubin MA, Polyak K, Chan J, Wang Y, Fletcher JA, Santagata S, Corso G, Roviello F, Shivdasani R, Kieran MW, Ligon KL, Stiles CD, Hahn WC, Meyerson ML, Garraway LA (2009) Profiling critical cancer gene mutations in clinical tumor samples. PLoS One 4:e7887PubMedCrossRefGoogle Scholar
- Marangoni E, Vincent-Salomon A, Auger N, Degeorges A, Assayag F, de Cremoux P, de Plater L, Guyader C, De Pinieux G, Judde JG, Rebucci M, Tran-Perennou C, Sastre-Garau X, Sigal-Zafrani B, Delattre O, Dieras V, Poupon MF (2007) A new model of patient tumor-derived breast cancer xenografts for preclinical assays. Clin Cancer Res 13:3989–3998PubMedCrossRefGoogle Scholar