title: Intrahepatic Tissue Implantation Represents a Favorable Approach for Establishing Orthotopic Transplantation Hepatocellular Carcinoma Mouse Models.
abstract: Mouse models are commonly used for studying hepatocellular carcinoma (HCC) biology and exploring new therapeutic interventions. Currently three main modalities of HCC mouse models have been extensively employed in pre-clinical studies including chemically induced, transgenic and transplantation models. Among them, transplantation models are preferred for evaluating in vivo drug efficacy in pre-clinical settings given the short latency, uniformity in size and close resemblance to tumors in patients. However methods used for establishing orthotopic HCC transplantation mouse models are diverse and fragmentized without a comprehensive comparison. Here, we systemically evaluate four different approaches commonly used to establish HCC mice in preclinical studies, including intravenous, intrasplenic, intrahepatic inoculation of tumor cells and intrahepatic tissue implantation. Four parameters--the latency period, take rates, pathological features and metastatic rates--were evaluated side-by-side. 100% take rates were achieved in liver with intrahepatic, intrasplenic inoculation of tumor cells and intrahepatic tissue implantation. In contrast, no tumor in liver was observed with intravenous injection of tumor cells. Intrahepatic tissue implantation resulted in the shortest latency with 0.5 cm (longitudinal diameter) tumors found in liver two weeks after implantation, compared to 0.1cm for intrahepatic inoculation of tumor cells. Approximately 0.1cm tumors were only visible at 4 weeks after intrasplenic inoculation. Uniform, focal and solitary tumors were formed with intrahepatic tissue implantation whereas multinodular, dispersed and non-uniform tumors produced with intrahepatic and intrasplenic inoculation of tumor cells. Notably, metastasis became visible in liver, peritoneum and mesenterium at 3 weeks post-implantation, and lung metastasis was visible after 7 weeks. T cell infiltration was evident in tumors, resembling the situation in HCC patients. Our study demonstrated that orthotopic HCC mouse models established via intrahepatic tissue implantation authentically reflect clinical manifestations in HCC patients pathologically and immunologically, suggesting intrahepatic tissue implantation is a preferable approach for establishing orthotopic HCC mouse models.
authors.affiliation: Department of Cell Biology and Research Centre of Basic Medical Science, Tianjin Medical University, Qixiangtai Road, Heping District, Tianjin, 300070, China.|Third Central Clinical College, Tianjin Medical University, Jintang Road, Hedong District, Tianjin, 300170, China.
authors.forename: Quan
authors.initials: Q
authors.lastname: Rao
authors.affiliation: Department of Cell Biology and Research Centre of Basic Medical Science, Tianjin Medical University, Qixiangtai Road, Heping District, Tianjin, 300070, China.|Tianjin Cancer Hospital, Tianjin Medical University, Huanhu West Road, Hexi District, Tianjin, 300000, China.
authors.forename: Abin
authors.initials: A
authors.lastname: You
authors.affiliation: Department of Cell Biology and Research Centre of Basic Medical Science, Tianjin Medical University, Qixiangtai Road, Heping District, Tianjin, 300070, China.
authors.forename: Zhenglong
authors.initials: Z
authors.lastname: Guo
authors.affiliation: Department of Cell Biology and Research Centre of Basic Medical Science, Tianjin Medical University, Qixiangtai Road, Heping District, Tianjin, 300070, China.
authors.forename: Bingfeng
authors.initials: B
authors.lastname: Zuo
authors.affiliation: Department of Cell Biology and Research Centre of Basic Medical Science, Tianjin Medical University, Qixiangtai Road, Heping District, Tianjin, 300070, China.
authors.forename: Xianjun
authors.initials: X
authors.lastname: Gao
authors.affiliation: Tianjin Cancer Hospital, Tianjin Medical University, Huanhu West Road, Hexi District, Tianjin, 300000, China.
authors.forename: Ti
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Third Central Clinical College, Tianjin Medical University, Jintang Road, Hedong District, Tianjin, 300170, China.|Department of Hepatobiliary Surgery, Key Laboratory of Artificial Cell, Institute for Hepatobiliary Diseases, Third Central Hospital, Tianjin Medical University, Jintang Road, Hedong District, Tianjin 300170, China.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Du
authors.affiliation: Third Central Clinical College, Tianjin Medical University, Jintang Road, Hedong District, Tianjin, 300170, China.
authors.forename: Chenxuan
authors.initials: C
authors.lastname: Wu
authors.affiliation: Department of Cell Biology and Research Centre of Basic Medical Science, Tianjin Medical University, Qixiangtai Road, Heping District, Tianjin, 300070, China.
authors.forename: HaiFang
authors.initials: H
authors.lastname: Yin
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000556:secondary*; D004195:Disease Models, Animal; D006651:Histocytochemistry; D006801:Humans; D007275:Injections, Intravenous; D008099:Liver / Q000473:pathology; D008113:Liver Neoplasms / Q000473:pathology*; D008168:Lung / Q000473:pathology; D008175:Lung Neoplasms / Q000556:secondary*; D008279:Magnetic Resonance Imaging; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009368:Neoplasm Transplantation / Q000379:methods; D010534:Peritoneal Neoplasms / Q000556:secondary*; D010537:Peritoneum / Q000473:pathology; D013154:Spleen / Q000473:pathology; D014407:Tumor Cells, Cultured / Q000637:transplantation*
references.citation: Vet J. 2009 Sep;181(3):336-9
references.pmid: 18583167
references.citation: Sci Bull (Beijing). 2015 Apr 1;60(8):762-772
references.pmid: 26029472
references.citation: Sci Rep. 2015;5:12315
references.pmid: 26189916
references.citation: Hepatology. 2013 Feb;57(2):667-77
references.pmid: 22996586
references.citation: Clin Cancer Res. 1996 Apr;2(4):695-706
references.pmid: 9816220
references.citation: World J Gastroenterol. 2004 Nov 1;10(21):3107-11
references.pmid: 15457553
references.citation: Toxicol Pathol. 2005;33(1):63-74
references.pmid: 15805057
references.citation: World J Gastroenterol. 2008 Dec 7;14(45):6915-23
references.pmid: 19058325
references.citation: Int J Clin Exp Pathol. 2013;6(5):816-20
references.pmid: 23638212
references.citation: Cancer Biol Ther. 2011 Oct 15;12(8):737-41
references.pmid: 21832881
references.citation: World J Gastroenterol. 2012 Dec 21;18(47):7087-92
references.pmid: 23323012
references.citation: Nat Rev Gastroenterol Hepatol. 2012 Jan;9(1):32-43
references.pmid: 22025031
references.citation: Liver Cancer. 2012 Nov;1(3-4):144-58
references.pmid: 24159579
references.citation: Int J Exp Pathol. 2009 Aug;90(4):367-86
references.pmid: 19659896
references.citation: Nature. 1983 Feb 10;301(5900):527-30
references.pmid: 6823332
references.citation: PLoS One. 2012;7(10):e48075
references.pmid: 23118928
references.citation: Int J Cancer. 1996 Apr 10;66(2):239-43
references.pmid: 8603818
references.citation: Tumour Biol. 2014 Dec;35(12):12561-6
references.pmid: 25204674
references.citation: Gastroenterology. 2012 May;142(6):1264-1273.e1
references.pmid: 22537432
references.citation: J Gastroenterol Hepatol. 2007 Mar;22(3):423-8
references.pmid: 17295777
references.citation: BMC Immunol. 2011;12:43
references.pmid: 21813021