Mouse Models of Hepatocellular Carcinoma: Classification, Advancement, and Application

Li, Sha; Huang, Fang; Ru, Guoqing; Wang, Yigang; Zhang, Bixiang; Chen, Xiaoping; Chu, Liang

doi:10.3389/fonc.2022.902820

Cited by 10 publications

(9 citation statements)

References 115 publications

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“…Our study used transgenic mouse models with several cancer‐specific mutations to induce pancreatic or liver cancer. These are well‐characterized genetically engineered mouse models in which tumors arise spontaneously and progress through well‐defined histopathological stages that closely recapitulate human disease, supporting the pathophysiological relevance of these murine models (Lee et al, 2016 ; Liu et al, 2022 ).…”

Section: Introductionmentioning

confidence: 71%

Evidence of sex differences in cancer‐related cardiac complications in mouse models of pancreatic and liver cancer

Gams

Nevarez

Perkail

et al. 2023

Physiological Reports

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Abnormal heart rate variability (HRV) is commonly observed in cancer patients who have undergone targeted therapy and/or surgery, yet the effects of cancer itself on cardiac function remain underexplored. Specifically, there is limited knowledge about sex‐specific manifestations of HRV in cancer patients. Transgenic mouse models are widely used to study different types of cancer. Here, we aimed to investigate the sex‐specific effects of cancer on cardiac function using transgenic mouse models of pancreatic and liver cancers. This study used male and female transgenic mice with cancer and wild‐type controls. Cardiac function was assessed by recording electrocardiograms in conscious mice. RR intervals were detected to determine HRV using time and frequency domain analyses. Histological analysis with Masson's trichrome staining was performed to determine structural changes. In females, increased HRV was observed in both pancreatic and liver cancer‐bearing mice. In contrast, in males, increased HRV was observed only in the liver cancer group. Male pancreatic cancer mice demonstrated autonomic balance shift showing an increase in parasympathetic to sympathetic tone. The heart rate (HR) was higher in control and liver cancer male mice groups than in females. Histological analysis did not show significant sex differences but suggested a higher degree of remodeling in liver cancer mice than in control, specifically in the right atrium and left ventricle. This study revealed sex differences in cancer's HR modulation. Specifically, female cancer mice had lower median HR and higher HRV. These findings indicate that sex must be considered when using HRV as a cancer biomarker.

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Section: Introductionmentioning

confidence: 71%

Evidence of sex differences in cancer‐related cardiac complications in mouse models of pancreatic and liver cancer

Gams

Nevarez

Perkail

et al. 2023

Physiological Reports

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“…Current rodent models, particularly mouse models, have limitations in fully replicating all stages of liver fibrosis, especially the transition to cirrhosis [4][5][6] . The diethylnitrosamine (DEN) induced rat model, commonly used to simulate human HCC in a relatively short time injection, does not completely mimic the progression from liver fibrosis to cirrhosis and subsequent HCC development [6][7][8] .…”

Section: Discussionmentioning

confidence: 99%

“…Current animal models, however, fall short in accurately representing all stages of liver fibrosis, particularly the transition to the cirrhotic stage [4][5][6] . In addition to not molecularly replicating genetic alterations observed in the clinic, even the widely used diethylnitrosamine-impaired rat (DEN rat) model, though effective in simulating human hepatocarcinogenesis, does not fully replicate the entire progression from liver fibrosis to cirrhosis and eventually to HCC [7][8][9] .…”

Section: Introductionmentioning

confidence: 99%

A rat model of cirrhosis with well-differentiated hepatocellular carcinoma induced by thioacetamide

Hu,

Kurihara,

Sun

et al. 2024

Preprint

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Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths, and commonly associated with hepatic fibrosis or cirrhosis. This study aims to establish a rat model mimicking the progression from liver fibrosis to cirrhosis and subsequently to HCC using thioacetamide (TAA). We utilized male Lewis rats, treating them with intra-peritoneal injections of TAA. These rats received bi-weekly injections of either 200 mg/kg TAA or saline (as a control) over a period of 34 weeks. The development of cirrhosis and hepatocarcinogenesis was monitored through histopathological examinations, biochemical markers, and immunohistochemical analyses. Our results demonstrated that chronic TAA administration induced cirrhosis and well-differentiated HCC, characterized by increased fibrosis, altered liver architecture, and enhanced hepatocyte proliferation. Biochemical analyses revealed significant alterations in liver function markers, including elevated alpha-fetoprotein (AFP) levels, without affecting kidney function or causing significant weight loss or mortality in rats. This TAA-induced cirrhosis and HCC rat model successfully replicates the clinical progression of human HCC, including liver function impairment and early-stage liver cancer characteristics. It presents a valuable tool for future research on the mechanisms of antitumor drugs in tumor initiation and development.

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“…The rst microscopic tumor foci appear in the liver about 90 days after DEN administration, and macroscopic tumors are already evident 180 days post-DEN. The percentage of HCC incidence and the number of tumor foci per liver are signi cantly higher in males than in females (3,4,15).…”

Section: Den-induced Hcc Modelmentioning

confidence: 98%

“…The histology and genetic signature of hepatocellular carcinoma (HCC) induced by diethylnitrosamine (DEN) in mice are strongly similar to those seen in humans (1,2). Another point of resemblance is the higher incidence and faster HCC tumor growth observed in males compared to females in both animal and clinical settings (3)(4)(5). The capacity of DEN to induce liver tumors has been associated with its activation into reactive metabolites that alkylate DNA through cytochrome P450-dependent pathways.…”

Section: Introductionmentioning

confidence: 99%

Different susceptibility to the development of hepatocellular carcinoma induced by diethylnitrosamine in female and male C3H mice

Montagna

Todero

Postma

et al. 2023

Preprint

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Histopathological features of hepatocellular carcinoma (HCC) induced by diethylnitrosamine (DEN) in mice displays strong similarities with those seen in humans, including the higher tumor prevalence in males than in females. Previous studies have demonstrated that continual production of the pro-inflammatory IL-6 by Kupffer cells is involved in the initiation and progression of DEN-induced HCC and that estrogen-mediated reduction of IL-6 secretion would decrease its incidence in females. However, the mechanisms by which different IL-6 concentrations affect tumor growth are not entirely understood. In this model, we demonstrated that the increased tumor growth observed in males accompanied significant liver damage and larger chronic inflammatory areas. Most tumors were placed into or close to senescent areas (detected by expression of β-galactosidase), and these areas were more extensive in DEN-treated males than in similarly-treated female mice. Further, different markers of systemic and regional immunosuppression (such as neutrophil-to-lymphocyte ratio, PD-1 expression in CD8 T cells, number of PD-L1 + myeloid-derived suppressor cells, etc.) were significantly higher in males than in females from the time the tumors started their exponential growth, suggesting that immunosuppressive mechanisms could contribute to the accelerated tumor growth observed in males. The relationship between chronic inflammation and immunosuppression has been previously documented. In contrast, little is known about the link between senescence and immunosuppression, raising the possibility that senescence may contribute to tumor growth by mechanisms other than immunological. Comparative studies between susceptible and resistant hosts to chemical carcinogenesis may help to unveil novel therapeutic strategies against cancer.

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Mouse Models of Hepatocellular Carcinoma: Classification, Advancement, and Application

Cited by 10 publications

References 115 publications

Evidence of sex differences in cancer‐related cardiac complications in mouse models of pancreatic and liver cancer

Evidence of sex differences in cancer‐related cardiac complications in mouse models of pancreatic and liver cancer

A rat model of cirrhosis with well-differentiated hepatocellular carcinoma induced by thioacetamide

Different susceptibility to the development of hepatocellular carcinoma induced by diethylnitrosamine in female and male C3H mice

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