Woodchuck hepatitis virus-induced carcinoma as a relevant natural model for therapy of human hepatoma

Gouillat, C.; Manganas, D.; Zoulim, Fabien; Vitrey, D; Saguier, G; Guillaud, Marylène; Ain, J. F.; Duque-Campos, René; Jamard, Catherine; Praves, M.; Trépo, Christian

doi:10.1016/s0168-8278(97)80468-0

Cited by 33 publications

(34 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Like most hepatitis B-induced HCCs in humans, they develop in their natural environment, with a background of active hepatitis, and immune escape mechanisms evolve that may negatively affect immunotherapeutical approaches (20). All these characteristics of woodchuck HCC and the outbred nature of the animals make the woodchuck a more clinically relevant animal model to study with the goal of developing prophylactic and therapeutical strategies for human HCC (7,21,22). Accordingly, our study used the woodchuck HCC model to investigate the feasibility and safety of adenovirus-mediated immunotherapy and antiangiogenic gene therapy for HCCs.…”

Section: Discussionmentioning

confidence: 99%

Combining antiangiogenic therapy with immunotherapy exerts better therapeutical effects on large tumors in a woodchuck hepatoma model

Huang

Lin

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Cytokine and antiangiogenic gene therapies have proved effective in implanted hepatocellular carcinoma (HCC) models in which small tumor burdens were established in small rodents. These models, however, may not reflect human HCCs, which are frequently detected at a stage when tumors are large and multifocal. In addition, HCC in patients is often associated with viral hepatitis. To investigate the effectiveness of a mixture type of gene therapy strategy on large tumor burdens, we used the woodchuck model in which woodchuck hepatitis virus-induced HCCs are large and multifocal, simulating the conditions in humans. Adenoviruses encoding antiangiogenic factors (pigment epithelium-derived factor and endostatin) or cytokines (GM-CSF and IL-12) were delivered via the hepatic artery separately or in combination into woodchuck livers bearing HCCs. Our results showed that the mixture type of strategy, which contained two cytokines and two antiangiogenic factors, had better antitumor effects on large tumors as compared with monotherapy either with antiangiogenic or cytokine genes. The immunotherapy recruited significant levels of CD3 + T cells that infiltrated the tumors, whereas the antiangiogenesis-based therapy significantly reduced tumor vasculature. The mixture type of gene therapy achieved both effects. In addition, it induced high levels of natural killer cells and apoptotic cells and reduced the levels of immunosuppressive effectors in the tumor regions. Hence, antiangiogenic therapy may provide the advantage of reducing immune tolerance in large tumors, making them more vulnerable to the immune reactions. Our study implies that in the future, the combination therapy may prove effective for the treatment of patients with advanced HCC.antiangiogenic therapy | cytokine gene therapy | gene therapy | hepatocellular carcinoma | multifocal liver tumors H epatocellular carcinoma (HCC) is the third leading cause of cancer mortality worldwide, with a high incidence in Asia (1, 2). The most important risk factor for HCC is the persistent infection by hepatitis B virus (HBV) or hepatitis C virus (3, 4). For patients with HCC, surgical resection may provide a significant survival advantage. However, many patients are diagnosed in the late stage and cannot tolerate hepatectomy because of advanced cancer or poor liver function reserve (5). Hence, effective adjuvant or palliative therapies still remain to be developed.To improve the treatment of HCC, preclinical animal studies are important because they allow us to evaluate the safety and effectiveness of unique therapeutical modalities. To date, animal models of HCC have been established mainly in rodents, either by implantation or by chemical induction. The primary liver tumor model, which develops spontaneously in its natural liver environment, is preferable to the implanted tumor models because it allows for the development of liver tumors that may exhibit immune escape properties, and multiple lesions are commonly seen in the primary liver tumor model. Nevertheless, none of ...

show abstract

Section: Discussionmentioning

confidence: 99%

Combining antiangiogenic therapy with immunotherapy exerts better therapeutical effects on large tumors in a woodchuck hepatoma model

Huang

Lin

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…Animal models close to the human pathology, such as chemically induced HCC in rats or woodchuck hepatitis virus-induced HCC in the woodchuck model, 11,26 could not be envisaged because the behavior of the rat regulatory elements in the murine context would not be relevant for the expression in vivo of the murine AFP promoter in a human HCC context. In addition, although the normal parenchyma shows some important proliferative ability under stress conditions, a relevant animal model mimicking the true mechanisms underlying the potential cell-to-cell contacts between HCC and normal hepatocytes should be very useful to study the bystander effect mediated killing of normal hepatocytes by GCV treated HCC cells.…”

Section: Discussionmentioning

confidence: 99%

Hepatoma cell-specific ganciclovir-mediated toxicity of a lentivirally transduced HSV-TkEGFP fusion protein gene placed under the control of rat alpha-fetoprotein gene regulatory sequences

et al. 2003

View full text Add to dashboard Cite

Suicide gene therapy combining herpes simplex virus thymidine kinase gene transfer and ganciclovir administration can be envisioned as a powerful therapeutical approach in the treatment of hepatocellular carcinoma; however, safety issues regarding transgene expression in parenchyma cells have to be addressed. In this study, we constructed LATKW, a lentiviral vector expressing the HSV-TkEGFP gene placed under the control of the promoter elements that control the expression of the rat alpha-fetoprotein, and assayed its specific expression in vitro in hepatocarcinoma and nonhepatocarcinoma human cell lines, and in epidermal growth factor stimulated human primary hepatocytes. Using LATKW, a strong expression of the transgene was found in transduced hepatocarcinoma cells compared to a very low expression in nonhepatocarcinoma human cell lines, as assessed by Northern blot, RT-PCR, FACS analysis and ganciclovir-mediated toxicity assay, and no expression was found in lentivirally transduced normal human hepatocytes. Altogether, these results demonstrate the possibility to use a lentivirally transduced expression unit containing the rat alpha-fetoprotein promoter to restrict the HSV-TK-mediated induced GCV sensitivity to human hepatocarcinoma cells.

show abstract

“…Although most of the clinical course of HCC in woodchucks is similar to that observed in humans, metastases, which commonly occur in human HCCs, are rare in woodchucks. 45 Lower levels of wk-IL-8 expression might therefore be one of the explanations for the rarity of HCC metastases in woodchucks. In human studies, it has been found that higher IL-8 expression is associated with HCCs having advanced pathologic stage, venous invasion and no tumor capsule.…”

Section: Il-8 In Woodchucks With Chronic Hepatitis and Hcc C-j Liu Et Almentioning

confidence: 99%

Characterization of interleukin 8 in woodchucks with chronic hepatitis B and hepatocellular carcinoma

Liu

et al. 2008

Genes Immun

View full text Add to dashboard Cite

The eastern woodchuck, Marmota monax, represents a useful animal model to study hepatitis B virus infection in humans. However, immunological studies in this model have been impeded by a lack of basic information about the components of the immune system such as cytokines and chemokines. To clarify the role(s) of interleukin 8 (IL-8) in chronic hepatitis B and hepatocellular carcinoma (HCC) in the woodchuck model, we cloned and characterized the woodchuck IL-8 cDNA and genomic DNA. Sequence analysis revealed that the organization of the wk-IL-8 gene is similar to that of the human IL-8 gene and consists of four exons and three introns. Woodchuck IL-8 protein exhibits the conserved ELRCXC motif of IL-8 and shows 87, 82, 82 and 79% similarity with rabbit, ovine, bovine and human IL-8 proteins, respectively. The biological activity of wk-IL-8 was demonstrated using neutrophil chemotaxis assays. Wk-IL-8 could be readily detected in both tumor and non-tumor tissues with higher expression in the non-tumor tissues in most cases. The results from this study will facilitate the investigation of IL-8 in the immunopathogenesis of hepadnavirus-related diseases by the woodchuck model.

show abstract

Woodchuck hepatitis virus-induced carcinoma as a relevant natural model for therapy of human hepatoma

Cited by 33 publications

References 28 publications

Combining antiangiogenic therapy with immunotherapy exerts better therapeutical effects on large tumors in a woodchuck hepatoma model

Combining antiangiogenic therapy with immunotherapy exerts better therapeutical effects on large tumors in a woodchuck hepatoma model

Hepatoma cell-specific ganciclovir-mediated toxicity of a lentivirally transduced HSV-TkEGFP fusion protein gene placed under the control of rat alpha-fetoprotein gene regulatory sequences

Characterization of interleukin 8 in woodchucks with chronic hepatitis B and hepatocellular carcinoma

Contact Info

Product

Resources

About