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Cancer Cell International
Published in: Cancer Cell International 1/2016

Open Access 01-12-2016 | Primary research

Comprehensive characterization of the patient-derived xenograft and the paralleled primary hepatocellular carcinoma cell line

Authors: Phyllis F. Y. Cheung, Chi Wai Yip, Linda W. C. Ng, Kwok Wai Lo, Chit Chow, Kui Fat Chan, Tan To Cheung, Siu Tim Cheung

Published in: Cancer Cell International | Issue 1/2016

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Abstract

Background

Hepatocellular carcinoma (HCC) is an aggressive cancer with high mortality and morbidity worldwide. The limited clinically relevant model has impeded the development of effective HCC treatment strategy. Patient-derived xenograft (PDX) models retain most of the characteristics of original tumors and were shown to be highly predictive for clinical outcomes. Notably, primary cell line models allow in-depth molecular characterization and high-throughput analysis. Combined usage of the two models would provide an excellent tool for systematic study of therapeutic strategies. Here, we comprehensively characterized the novel PDX and the paralleled primary HCC cell line model.

Methods

Tumor tissues were collected from HCC surgical specimens. HCC cells were sorted for in vivo PDX and in vitro cell line establishment by the expression of hepatic cancer stem cell marker to enhance cell viability and the rate of success on subsequent culture. The PDX and its matching primary cell line were authenticated and characterized in vitro and in vivo.

Results

Among the successful cases for generating PDXs and primary cells, HCC40 is capable for both PDX and primary cell line establishment, which were then further characterized. The novel HCC40-PDX and HCC40-CL exhibited consistent phenotypic characteristics as the original tumor in terms of HBV protein and AFP expressions. In common with HCC40-PDX, HCC40-CL was tumorigenic in immunocompromised mice. The migration ability in vitro and metastatic properties in vivo echoed the clinical feature of venous infiltration. Genetic profiling by short tandem repeat analysis and p53 mutation pattern consolidated that both the HCC40-PDX and HCC40-CL models were derived from the HCC40 clinical specimen.

Conclusions

The paralleled establishment of PDX and primary cell line would serve as useful models in comprehensive studies for HCC pathogenesis and therapeutics development for personalized treatment.
Appendix
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Literature
1.
Singal AG, El-Serag HB. Hepatocellular carcinoma from epidemiology to prevention: translating knowledge into practice. Clin Gastroenterol Hepatol. 2015;13(12):2140–51.CrossRefPubMed
2.
Bruix J, Reig M, Sherman M. Evidence-based diagnosis, staging, and treatment of patients with hepatocellular carcinoma. Gastroenterology. 2016;150(4):835–53.CrossRefPubMed
3.
Johnson JI, Decker S, Zaharevitz D, Rubinstein LV, Venditti JM, Schepartz S, Kalyandrug S, Christian M, Arbuck S, Hollingshead M, Sausville EA. Relationships between drug activity in NCI preclinical in vitro and in vivo models and early clinical trials. Br J Cancer. 2001;84(10):1424–31.CrossRefPubMedPubMedCentral
4.
Gillet JP, Calcagno AM, Varma S, Marino M, Green LJ, Vora MI, Patel C, Orina JN, Eliseeva TA, Singal V, Padmanabhan R, Davidson B, Ganapathi R, Sood AK, Rueda BR, Ambudkar SV, Gottesman MM. Redefining the relevance of established cancer cell lines to the study of mechanisms of clinical anti-cancer drug resistance. Proc Natl Acad Sci USA. 2011;108(46):18708–13.CrossRefPubMedPubMedCentral
5.
Hausser HJ, Brenner RE. Phenotypic instability of Saos-2 cells in long-term culture. Biochem Biophys Res Commun. 2005;333(1):216–22.CrossRefPubMed
6.
7.
Tentler JJ, Tan AC, Weekes CD, Jimeno A, Leong S, Pitts TM, Arcaroli JJ, Messersmith WA, Eckhardt SG. Patient-derived tumour xenografts as models for oncology drug development. Nat Rev Clin Oncol. 2012;9(6):338–50.CrossRefPubMedPubMedCentral
8.
Michelhaugh SK, Guastella AR, Varadarajan K, Klinger NV, Parajuli P, Ahmad A, Sethi S, Aboukameel A, Kiousis S, Zitron IM, Ebrahim SA, Polin LA, Sarkar FH, Bollig-Fischer A, Mittal S. Development of patient-derived xenograft models from a spontaneously immortal low-grade meningioma cell line, KCI-MENG1. J Transl Med. 2015;13:227.CrossRefPubMedPubMedCentral
9.
Damhofer H, Ebbing EA, Steins A, Welling L, Tol JA, Krishnadath KK, van Leusden T, van de Vijver MJ, Besselink MG, Busch OR, Berge Henegouwen O, Meijer SL, Dijk F, Medema JP, van Laarhoven HW, Bijlsma MF. Establishment of patient-derived xenograft models and cell lines for malignancies of the upper gastrointestinal tract. J Transl Med. 2015;13:115.CrossRefPubMedPubMedCentral
10.
Sivanand S, Pena-Llopis S, Zhao H, Kucejova B, Spence P, Pavia-Jimenez A, Yamasaki T, McBride DJ, Gillen J, Wolff NC,  Morlock L, Lotan Y, Raj GV, Sagalowsky A, Margulis V, Cadeddu JA, Ross MT, Bentley, Kabbani W, Xie XJ, Kapur P, Williams NS, Brugarolas J. A validated tumorgraft model reveals activity of dovitinib against renal cell carcinoma. Sci Transl Med. 2012;4(137):137ra75.CrossRefPubMedPubMedCentral
11.
Keysar SB, Astling DP, Anderson RT, Vogler BW, Bowles DW, Morton JJ, Paylor JJ, Glogowska MJ, Le PN, Eagles-Soukup JR, Kako SL, Takimoto SM, Sehrt DB, Umpierrez A, Pittman MA, Macfadden SM, Helber RM, Peterson S, Hausman DF, Said S, Leem TH, Goddard JA, Arcaroli JJ, Messersmith WA, Robinson WA, Hirsch FR, Varella-Garcia M, Raben D, Wang XJ, Song JI, Tan AC, Jimeno A. A patient tumor transplant model of squamous cell cancer identifies PI3 K inhibitors as candidate therapeutics in defined molecular bins. Mol Oncol. 2013;7(4):776–90.CrossRefPubMedPubMedCentral
12.
Bertotti A, Migliardi G, Galimi F, Sassi F, Torti D, Isella C, Corà D, Di Nicolantonio F, Buscarino M, Petti C, Ribero D, Russolillo N, Muratore A, Massucco P, Pisacane A, Molinaro L, Valtorta E, Sartore-Bianchi A, Risio M, Capussotti L, Gambacorta M, Siena S, Medico E, Sapino A, Marsoni S, Comoglio PM, Bardelli A, Trusolino L. A molecularly annotated platform of patient-derived xenografts (“xenopatients”) identifies HER2 as an effective therapeutic target in cetuximab-resistant colorectal cancer. Cancer Discov. 2011;1(6):508–23.CrossRefPubMed
13.
Migliardi G, Sassi F, Torti D, Galimi F, Zanella ER, Buscarino M, ibero D, Muratore A, Massucco P, Pisacane A, Risio M, Capussotti L, Marsoni S, Di Nicolantonio F, Bardelli A, Comoglio PM, Trusolino L, Bertotti A. Inhibition of MEK and PI3 K/mTOR suppresses tumor growth but does not cause tumor regression in patient-derived xenografts of RAS-mutant colorectal carcinomas. Clin Cancer Res. 2012;18(9):2515–25.CrossRefPubMed
14.
Julien S, Merino-Trigo A, Lacroix L, Pocard M, Goere D, Mariani P, Landron S, Bigot L, Nemati F, Dartigues P, Weiswald LB, Lantuas D, Morgand L, Pham E, Gonin P, Dangles-Marie V, Job B, Dessen P, Bruno A, Pierré A, De Thé H, Soliman H, Nunes M, Lardier G, Calvet L, Demers B, Prévost G, Vrignaud P, Roman-Roman S, Duchamp O, Berthet C. Characterization of a large panel of patient-derived tumor xenografts representing the clinical heterogeneity of human colorectal cancer. Clin Cancer Res. 2012;18(19):5314–28.CrossRefPubMed
15.
Garrido-Laguna I, Uson M, Rajeshkumar NV, Tan AC, de Oliveira E, Karikari C, Villaroel MC, Salomon A, Taylor G, Sharma R, Hruban RH, Maitra A, Laheru D, Rubio-Viqueira B, Jimeno A, Hidalgo M. Tumor engraftment in nude mice and enrichment in stroma- related gene pathways predict poor survival and resistance to gemcitabine in patients with pancreatic cancer. Clin Cancer Res. 2011;17(17):5793–800.CrossRefPubMedPubMedCentral
16.
Gao H, Korn JM, Ferretti S, Monahan JE, Wang Y, Singh M, Zhang C, Schnell C, Yang G, Zhang Y, Balbin OA, Barbe S, Cai H, Casey F, Chatterjee S, Chiang DY, Chuai S, Cogan SM, Collins SD, Dammassa E, Ebel N, Embry M, Green J, Kauffmann A, Kowal C, Leary RJ, Lehar J, Liang Y, Loo A, Lorenzana E, RobertMcDonald E 3rd, McLaughlin ME, Merkin J, Meyer R, Naylor TL, Patawaran M, Reddy A, Röelli C, Ruddy DA, Salangsang F, Santacroce F, Singh AP, Tang Y, Tinetto W, Tobler S, Velazquez R, Venkatesan K, Von Arx F, Wang HQ, Wang Z, Wiesmann M, Wyss D, Xu F, Bitter H, Atadja P, Lees E, Hofmann F, Li E, Keen N, Cozens R, Jensen MR, Pryer NK, Williams JA, Sellers WR. High-throughput screening using patient-derived tumor xenografts to predict clinical trial drug response. Nat Med. 2015;21(11):1318–25.CrossRefPubMed
17.
Zhang X, Claerhout S, Prat A, Dobrolecki LE, Petrovic I, Lai Q, Landis MD, Wiechmann L, Schiff R, Giuliano M, Wong H, Fuqua SW, Contreras A, Gutierrez C, Huang J, Mao S, Pavlick AC, Froehlich AM, Wu MF, Tsimelzon A, Hilsenbeck SG, Chen ES, Zuloaga P, Shaw CA, Rimawi MF, Perou CM, Mills GB, Chang JC, Lewis MT. A renewable tissue resource of phenotypically stable, biologically and ethnically diverse, patient-derived human breast cancer xenograft models. Cancer Res. 2013;73(15):4885–97.CrossRefPubMedPubMedCentral
18.
Fichtner I, Rolff J, Soong R, Hoffmann J, Hammer S, Sommer A, Becker M, Merk J. Establishment of patient-derived non-small cell lung cancer xenografts as models for the identification of predictive biomarkers. Clin Cancer Res. 2008;14(20):6456–68.CrossRefPubMed
19.
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, Diéras V, Poupon MF. A new model of patient tumor-derived breast cancer xenografts for preclinical assays. Clin Cancer Res. 2007;13(13):3989–98.CrossRefPubMed
20.
Hidalgo M, Amant F, Biankin AV, Budinska E, Byrne AT, Caldas C, Clarke RB, de Jong S, Jonkers J, Mælandsmo GM, Roman-Roman S, Seoane J, Trusolino L, Villanueva A. Patient-derived xenograft models: an emerging platform for translational cancer research. Cancer Discov. 2014;4(9):998–1013.CrossRefPubMedPubMedCentral
21.
Kamiyama H, Rauenzahn S, Shim JS, Karikari CA, Feldmann G, Hua L, Kamiyama M, Schuler FW, Lin MT, Beaty RM, Karanam B, Liang H, Mullendore ME, Mo G, Hidalgo M, Jaffee E, Hruban RH, Jinnah HA, Roden RB, Jimeno A, Liu JO, Maitra A, Eshleman JR. Personalized chemotherapy profiling using cancer cell lines from selectable mice. Clin Cancer Res. 2013;19(5):1139–46.CrossRefPubMedPubMedCentral
22.
Dalerba P, Kalisky T, Sahoo D, Rajendran PS, Rothenberg ME, Leyrat AA, Sim S, Okamoto J, Johnston DM, Qian D, Zabala M, Bueno J, Neff NF, Wang J, Shelton AA, Visser B, Hisamori S, Shimono Y, van de Wetering M, Clevers H, Clarke MF, Quake SR. Single-cell dissection of transcriptional heterogeneity in human colon tumors. Nat Biotechnol. 2011;29(12):1120–7.CrossRefPubMedPubMedCentral
23.
Cheung PF, Cheng CK, Wong NC, Ho JC, Yip CW, Lui VC, Cheung AN, Fan ST, Cheung ST. Granulin-epithelin precursor is an oncofetal protein defining hepatic cancer stem cells. PLoS ONE. 2011;6(12):e28246.CrossRefPubMedPubMedCentral
24.
Cheung PF, Yip CW, Ng LW, Lo KW, Wong N, Choy KW, Chow C, Chan KF, Cheung TT, Poon RT, Fan ST, Cheung ST. Establishment and characterization of a novel primary hepatocellular carcinoma cell line with metastatic ability in vivo. Cancer Cell Int. 2014;14(1):103.CrossRefPubMedPubMedCentral
25.
Kondo J, Endo H, Okuyama H, Ishikawa O, Iishi H, Tsujii M, Ohue M, Inoue M. Retaining cell-cell contact enables preparation and culture of spheroids composed of pure primary cancer cells from colorectal cancer. Proc Natl Acad Sci USA. 2011;108(15):6235–40.CrossRefPubMedPubMedCentral
26.
Cheung PF, Cheung TT, Yip CW, Ng LW, Fung SW, Lo CM, Fan ST, Cheung ST. Hepatic cancer stem cell marker granulin-epithelin precursor and β-catenin expression associate with recurrence in hepatocellular carcinoma. Oncotarget. 2016;1:7803.
27.
Cheung PF, Yip CW, Wong NC, Fong DY, Ng LW, Wan AM, Wong CK, Cheung TT, Ng IO, Poon RT, Fan ST, Cheung ST. Granulin-epithelin precursor renders hepatocellular carcinoma cells resistant to natural killer cytotoxicity. Cancer Immunol Res. 2014;2(12):1209–19.CrossRefPubMed
28.
Derksen PW, Liu X, Saridin F, van der Gulden H, Zevenhoven J, Evers B, van Beijnum JR, Griffioen AW, Vink J, Krimpenfort P, Peterse JL, Cardiff RD, Berns A, Jonkers J. Somatic inactivation of E-cadherin and p53 in mice leads to metastatic lobular mammary carcinoma through induction of anoikis resistance and angiogenesis. Cancer Cell. 2006;10(5):437–49.CrossRefPubMed
29.
Perl AK, Wilgenbus P, Dahl U, Semb H, Christofori G. A causal role for E-cadherin in the transition from adenoma to carcinoma. Nature. 1998;392(6672):190–3.CrossRefPubMed
30.
Frixen UH, Behrens J, Sachs M, Eberle G, Voss B, Warda A, Löchner D, Birchmeier W. E-cadherin-mediated cell-cell adhesion prevents invasiveness of human carcinoma cells. J Cell Biol. 1991;113(1):173–85.CrossRefPubMed
31.
Ho JC, Ip YC, Cheung ST, Lee YT, Chan KF, Wong SY, Fan ST. Granulin-epithelin precursor as a therapeutic target for hepatocellular carcinoma. Hepatology. 2008;47(5):1524–32.CrossRefPubMed
32.
Wong NC, Cheung PF, Yip CW, Chan KF, Ng IO, Fan ST, Cheung ST. Antibody against granulin-epithelin precursor sensitizes hepatocellular carcinoma to chemotherapeutic agents. Mol Cancer Ther. 2014;13(12):3001–12.CrossRefPubMed
33.
Rubio-Viqueira B, Jimeno A, Cusatis G, Zhang X, Iacobuzio-Donahue C, Karikari C, Shi C, Danenberg K, Danenberg PV, Kuramochi H, Tanaka K, Singh S, Salimi-Moosavi H, Bouraoud N, Amador ML, Altiok S, Kulesza P, Yeo C, Messersmith W, Eshleman J, Hruban RH, Maitra A, Hidalgo M. An in vivo platform for translational drug development in pancreatic cancer. Clin Cancer Res. 2006;12(15):4652–61.CrossRefPubMed
34.
Tang ZY, Ye SL, Liu YK, Qin LX, Sun HC, Ye QH, Wang L, Zhou J, Qiu SJ, Li Y, Ji XN, Liu H, Xia JL, Wu ZQ, Fan J, Ma ZC, Zhou XD, Lin ZY, Liu KD. A decade’s studies on metastasis of hepatocellular carcinoma. J Cancer Res Clin Oncol. 2004;130(4):187–96.CrossRefPubMed
35.
Winter JM, Ting AH, Vilardell F, Gallmeier E, Baylin SB, Hruban RH, Kern SE, Iacobuzio-Donahue CA. Absence of E-cadherin expression distinguishes noncohesive from cohesive pancreatic cancer. Clin Cancer Res. 2008;14(2):412–8.CrossRefPubMed
36.
Hashiguchi M, Ueno S, Sakoda M, Iino S, Hiwatashi K, Minami K, Ando K, Mataki Y, Maemura K, Shinchi H, Ishigami S, Natsugoe S. Clinical implication of ZEB-1 and E-cadherin expression in hepatocellular carcinoma (HCC). BMC Cancer. 2013;13:572.CrossRefPubMedPubMedCentral
37.
Khanna C, Jaboin JJ, Drakos E, Tsokos M, Thiele CJ. Biologically relevant orthotopic neuroblastoma xenograft models: primary adrenal tumor growth and spontaneous distant metastasis. Vivo. 2002;16(2):77–85.
38.
Hoffman RM. Patient-derived orthotopic xenografts: better mimic of metastasis than subcutaneous xenografts. Nat Rev Cancer. 2015;15(8):451–2.CrossRefPubMed
39.
Liu J, Ma Q, Zhang M, Wang X, Zhang D, Li W, Wang F, Wu E. Alterations of TP53 are associated with a poor outcome for patients with hepatocellular carcinoma: evidence from a systematic review and meta-analysis. Eur J Cancer. 2012;48(15):2328–38.CrossRefPubMedPubMedCentral
40.
Yuan RH, Jeng YM, Chen HL, Lai PL, Pan HW, Hsieh FJ, Lin CY, Lee PH, Hsu HC. Stathmin overexpression cooperates with p53 mutation and osteopontin overexpression, and is associated with tumour progression, early recurrence, and poor prognosis in hepatocellular carcinoma. J Pathol. 2006;209(4):549–58.CrossRefPubMed
41.
Terris B, Laurent-Puig P, Belghitti J, Degott C, Henin D, Flejou JF. Prognostic influence of clinicopathologic features, DNA-ploidy, CD44H and p53 expression in a large series of resected hepatocellular carcinoma in France. Int J Cancer. 1997;74(6):614–9.CrossRefPubMed
42.
Ozaki T, Nakagawara A. The attractive tumor suppressor in the cancer research field. J Biomed Biotechnol. 2011;2011:603925.CrossRefPubMed
43.
Mukherjee S, Kong J, Brat DJ. Cancer stem cell division: when the rules of asymmetry are broken. Stem Cells Dev. 2015;24(4):405–16.CrossRefPubMed
44.
Ma S, Chan KW, Hu L, Lee TK, Wo JY, Ng IO, Zheng BJ, Guan XY. Identification and characterization of tumorigenic liver cancer stem/progenitor cells. Gastroenterology. 2007;132(7):2542–56.CrossRefPubMed
45.
Lee TK, Castilho A, Cheung VC, Tang KH, Ma S, Ng IO. CD24(+) liver tumor-initiating cells drive self-renewal and tumor initiation through STAT3-mediated NANOG regulation. Cell Stem Cell. 2011;9(1):50–63.CrossRefPubMed
Metadata
Title
Comprehensive characterization of the patient-derived xenograft and the paralleled primary hepatocellular carcinoma cell line
Authors
Phyllis F. Y. Cheung
Chi Wai Yip
Linda W. C. Ng
Kwok Wai Lo
Chit Chow
Kui Fat Chan
Tan To Cheung
Siu Tim Cheung
Publication date
01-12-2016
Publisher
BioMed Central
Published in
Cancer Cell International / Issue 1/2016
Electronic ISSN: 1475-2867
DOI
https://doi.org/10.1186/s12935-016-0322-5

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