Alpha-fetoprotein-thymidine kinase–luciferase knockin mice: A novel model for dual modality longitudinal imaging of tumorigenesis in liver

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• 作者：Xincheng Lu¹ ; ² ; ^† ; ; Hong Guo¹ ; ³ ; ^† ; ; Joseph Molter⁴ ; Hui Miao¹ ; ³ ; Lizabeth Gerber³ ; Yiduo Hu¹ ; ² ; Ellen L. Barnes¹ ; ² ; Hannes Vogel⁵ ; Zhenghong Lee¹ ; ⁴ ; ⁶ ; Guangbin Luo¹ ; ² ; ^{guangbin.luo@case.edu"" rel=""nofollow} ; Bingcheng Wang¹ ; ² ; ⁷ ; ^{bxw14@case.edu"" rel=""nofollow}
• 关键词：Positron emission tomography ; Bioluminescence imaging ; Hepatocarcinogenesis ; Hepatocellular carcinoma ; Testes
• 刊名：Journal of Hepatology
• 出版年：2011
• 出版时间：July 2011
• 年：2011
• 卷：55
• 期：1
• 页码：96-102
• 全文大小：1496 K

文摘

Background & Aims

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

Knockin mice were established by placing a thymidine kinase (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.