title: Alpha-fetoprotein-thymidine kinase-luciferase knockin mice: a novel model for dual modality longitudinal imaging of tumorigenesis in liver.
abstract: OBJECTIVE
  Hepatocellular carcinoma (HCC) is frequently a lethal disease and one of the few malignancies that is still increasing in incidence around the world. Better animal models are highly desired to investigate the molecular basis of HCC and to develop novel therapeutic strategies. Alpha-fetoprotein (Afp) gene is expressed in fetal liver, silenced soon after birth, and highly re-expressed in hepatocellular carcinomas (HCC). We aimed to take advantage of the dramatic re-expression of the Afp gene in HCC to develop a hepatocarcinogenesis reporter (HCR) mouse model for dual-modality, longitudinal in vivo imaging of liver tumor development, and progression.
  
  
  METHODS
  Knock in mice were established by placing a thymidinekinase (tk)-luciferase (luc) reporter gene cassette under the transcriptional control of the endogenous Afp promoter. DEN, a liver carcinogen, was used to induce liver tumors, which was monitored by both luc-based bioluminescent (BL) and tk-based positron emission tomography (PET) imaging.
  
  
  RESULTS
  The expression profile of luc was identical to that of the endogenous Afp gene during development. As early as 2 months after the exposure to DEN, BLI revealed multifocal signals in the liver, long before the appearance of histologically apparent neoplastic lesions. By 6 months, BL and PET dual imaging showed strong signals in malignant HCC. By serendipity, a strong BL signal was also detected in adult testes, a previously unknown site of Afp expression.
  
  
  CONCLUSIONS
  The HCR model enables longitudinal monitoring of liver tumor development and progression, providing a powerful tool in developing chemoprevention and therapeutic strategies for HCC.
authors.affiliation: Case Comprehensive Cancer Centre, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: Xincheng
authors.initials: X
authors.lastname: Lu
authors.forename: Hong
authors.initials: H
authors.lastname: Guo
authors.forename: Joseph
authors.initials: J
authors.lastname: Molter
authors.forename: Hui
authors.initials: H
authors.lastname: Miao
authors.forename: Lizabeth
authors.initials: L
authors.lastname: Gerber
authors.forename: Yiduo
authors.initials: Y
authors.lastname: Hu
authors.forename: Ellen L
authors.initials: EL
authors.lastname: Barnes
authors.forename: Hannes
authors.initials: H
authors.lastname: Vogel
authors.forename: Zhenghong
authors.initials: Z
authors.lastname: Lee
authors.forename: Guangbin
authors.initials: G
authors.lastname: Luo
authors.forename: Bingcheng
authors.initials: B
authors.lastname: Wang
mesh_terms: D000818:Animals; D004052:Diethylnitrosamine / Q000633:toxicity; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D055879:Gene Knock-In Techniques; D017930:Genes, Reporter; D006801:Humans; D008114:Liver Neoplasms, Experimental / Q000000981:diagnostic imaging / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D008156:Luciferases / Q000235:genetics*; D049449:Luminescence; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D049268:Positron-Emission Tomography; D011230:Precancerous Conditions / Q000000981:diagnostic imaging / Q000209:etiology / Q000235:genetics / Q000473:pathology; D013937:Thymidine Kinase / Q000235:genetics*; D000509:alpha-Fetoproteins / Q000235:genetics*
chemical_list: D000509:alpha-Fetoproteins; D004052:Diethylnitrosamine; D008156:Luciferases; D013937:Thymidine Kinase