Table 1.
Synopsis of chemically induced HCC model with metastasis.
| Chemical agents | Characteristics | Metastasis | Comments | References (Year) |
|---|---|---|---|---|
| DMN induced model | Months 6.5–10: primary hepatic tumor development | Pulmonary (7/20) and intra-abdominal (3/20) metastasis | The first to provide methods for chemical agent induced HCC model | Magee et al (1956)15 |
| DEN and 2-AAF + PH induced model | Months 8: 68%–71% HCC; | 9.1%–16.7% metastatic rate | Starting the method of “two-step” (initiation, promotion) model; DEN alone could not induce carcinogenesis; |
Solt et al (1983)17 |
| [PH + B(a)P] + [2-AAF + CCl4] induced model | Months 18: 82% (14/17) HCC | 23.5% (4/17) pulmonary metastasis | ||
| [PH + 1,2-DMH] + [2-AAF + CCl4] induced model | Months 18: 67% (8/12) HCC | 16.7% (2/12) pulmonary metastasis | ||
| DEN induced model | Months 11-: 100% HCC | 25%–50% metastasis rate in B6C3F1 mice; 0%–33% metastasis rate in C3AF1 mice |
Revealing heterogeneity between different species; Younger mice have faster HCC development than older mice |
Vesselinovitch et al (1984)20 |
| NMOR induced model | Months 25: 63% (15/24) HCC (NMOR 100 mg/L); Months 40: 67% (16/24) HCC (NMOR 40 mg/L) |
NMOR 100 mg/L: 4.2% metastatic rate; NMOR 40 mg/L: 29.2% metastatic rate |
Focusing on the dose response in F344 rats when administered with NMOR | Lijinsky et al (1988)18 |
| DEN + PB induced model | Months 10: 30% (6/20) HCC | NA | PB shortened the time to HCC appearance | Klaunig et al (1988)23 |
| DEN + NMOR induced model | Months 4: 100% (15/15) HCC | Months 7: 100% (15/15) pulmonary metastasis | Providing an optimal method for the inducing of HCC with significant pulmonary metastasis | Masui et al (1997)14 |
| DEN + NMOR induced model | Months 2: 60% (9/15) HCC; Months 4: 100% (13/13) HCC; Months 5.5: 94% (17/18) HCC |
Months 2: 0% (0/15) pulmonary metastasis; Months 4: 69% (9/13) pulmonary metastasis; Months 5.5: 84% (16/19) pulmonary metastasis |
Established relatively stable HCC model for studies on metastasis; Providing experience for metastatic model construction |
Futakuchi et al (1999)19 |
| NNM induced model | Months 6.8: 100% (15/15) HCC; | Months 7: 87% (13/15) metastasis rate | WS/Shi was the most sensitive species to NNM compared with SD/gShi, and F344/DuCrj rats | Murai et al (2000)24 |
| DEN + PB induced model | Months 5: 67% (6/9) macroscopic hepatic masses; Months 9: 100% (9/9) macroscopic hepatic masses |
NA | PB did not influence the incidence of macroscopic hepatic masses | Goldsworthy et al (2002)25 |
| DEN + NMOR induced model | Months 3.5: HCC was observed; Months 5: 100% HCC |
Months 5.5: first pulmonary metastasis; Months 9: 60% pulmonary metastasis; Months 10: 100% pulmonary metastasis |
Modifying the experimental protocol to improve survival and to establish a better animal metastasis model | Yoshino et al (2005)22 |
| DEN in GDF-15 deleted mice | Months 6: 80% (16/20) HCC | No metastasis | GDF-15 had no apparent effect on HCC tumor formation rate, growth rate, or invasiveness in DEN-induced HCC | Zimmers et al (2008)26 |
| DEN in ATM mutated mice | Months 1.3: development of HCC; Months 12: 100% HCC |
Pulmonary metastasis in 50% of ATM+/+ and 52% of ATM+/− mice; Months 12: 100% metastasizing HCC in wild type or ATM+/- mice |
Hepatocarcinogenesis is abrogated in ATM-deficient mice | Teoh et al (2010)27 |
| DEN + PB | Months 8: microscopically and macroscopically detectable tumors; Months 14: HCC |
NA | Exploring the tumor genomes of DEN induced HCC for the first time; Beta-catenin mutation and activation of the Wnt/β-catenin pathway were not involved in tumor initiation of this model |
Aleksic et al (2011)28 |
Abbreviations: HCC, hepatocellular carcinoma; DMN, dimethylnitrosamine; DEN, diethylnitrosamine; 2-AAF, 2-acetylaminofluorene; PH, partial hepatectomy; B(a)P, benzo(a)pyrene; 1,2-DMH, 1,2-dimethylhydrazine; NMOR, nitrosomorpholine; PB, phenobarbital; NNM, N-nitrosomorpholine; GDF-15, Growth/differentiation factor-15; ATM, ataxia telangiectasia mutated.