Differential antitumor effect of interleukin-12 family cytokines on orthotopic hepatocellular carcinoma

Chia Hui Lo, Chia Ming Chang, Shih Wen Tang, Wen Yu Pan, Cheng Chieh Fang, Yin Chen, Ping Yi Wu, Kai Yun Chen, Hsin I. Ma, Xiao Xiao, Mi Hua Tao

Research output: Contribution to journalArticle

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Abstract

Background: Hepatocellular carcinoma (HCC) is one of the most difficult cancers to treat. The interleukin (IL)-12 family cytokines, including IL-12, IL-23 and IL-27, display overlapping, but not redundant, roles in regulating lymphocyte subpopulations. IL-12 is known as a potent antitumor cytokine, whereas the results of the antitumor effect of IL-23 and IL-27 are inconsistent. The present study aimed to directly compare the relative antitumor efficacy of these three IL-12 family cytokines on HCC. Methods: A murine orthotopic BNL HCC model, in which the tumor is located in an environment heavily populated with different lymphocyte subsets, was established. The hepatotropic adeno-associated virus serotype 8 (AAV8) vector was used to deliver the cytokine genes aiming to achieve sustained cytokine expression in the liver. Results: AAV8/IL-12 treatment significantly reduced hepatic metastases and prolonged survival time, whereas treatment with AAV8/IL-23 or AAV8/IL-27 had only moderate antitumor effects at a high dose. The antitumor efficacy of these cytokines was positively correlated with their ability to regulate hepatic T cells, natural killer cells and natural killer T cells, with IL-12 greatly increasing the number and activation status of these cells, whereas IL-27 had no effect and IL-23 had a negative effect. AAV8/IL-12 treatment also resulted in a marked decrease in tumor vessel density, which was not observed with AAV8/IL-23 and AAV8/IL-27 treatment. Conclusions: The data obtained in the present study highlight the importance of local lymphocytes and anti-angiogenesis for influencing the antitumor activity of these three IL-12 family cytokines and suggest that IL-12 is the best candidate for treating HCC.

Original languageEnglish
Pages (from-to)423-434
Number of pages12
JournalJournal of Gene Medicine
Volume12
Issue number5
DOIs
Publication statusPublished - May 2010
Externally publishedYes

Fingerprint

Interleukin-12
Dependovirus
Hepatocellular Carcinoma
Interleukin-27
Interleukin-23
Cytokines
Lymphocyte Subsets
Neoplasms
Natural Killer T-Cells
Liver
Serogroup
Natural Killer Cells
Hepatocytes
Lymphocytes
Neoplasm Metastasis
T-Lymphocytes

Keywords

  • Adeno-associated virus
  • Hepatocellular carcinoma
  • IL-12
  • IL-23
  • IL-27

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Molecular Medicine
  • Genetics(clinical)
  • Drug Discovery

Cite this

Lo, C. H., Chang, C. M., Tang, S. W., Pan, W. Y., Fang, C. C., Chen, Y., ... Tao, M. H. (2010). Differential antitumor effect of interleukin-12 family cytokines on orthotopic hepatocellular carcinoma. Journal of Gene Medicine, 12(5), 423-434. https://doi.org/10.1002/jgm.1452

Differential antitumor effect of interleukin-12 family cytokines on orthotopic hepatocellular carcinoma. / Lo, Chia Hui; Chang, Chia Ming; Tang, Shih Wen; Pan, Wen Yu; Fang, Cheng Chieh; Chen, Yin; Wu, Ping Yi; Chen, Kai Yun; Ma, Hsin I.; Xiao, Xiao; Tao, Mi Hua.

In: Journal of Gene Medicine, Vol. 12, No. 5, 05.2010, p. 423-434.

Research output: Contribution to journalArticle

Lo, CH, Chang, CM, Tang, SW, Pan, WY, Fang, CC, Chen, Y, Wu, PY, Chen, KY, Ma, HI, Xiao, X & Tao, MH 2010, 'Differential antitumor effect of interleukin-12 family cytokines on orthotopic hepatocellular carcinoma', Journal of Gene Medicine, vol. 12, no. 5, pp. 423-434. https://doi.org/10.1002/jgm.1452
Lo, Chia Hui ; Chang, Chia Ming ; Tang, Shih Wen ; Pan, Wen Yu ; Fang, Cheng Chieh ; Chen, Yin ; Wu, Ping Yi ; Chen, Kai Yun ; Ma, Hsin I. ; Xiao, Xiao ; Tao, Mi Hua. / Differential antitumor effect of interleukin-12 family cytokines on orthotopic hepatocellular carcinoma. In: Journal of Gene Medicine. 2010 ; Vol. 12, No. 5. pp. 423-434.
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abstract = "Background: Hepatocellular carcinoma (HCC) is one of the most difficult cancers to treat. The interleukin (IL)-12 family cytokines, including IL-12, IL-23 and IL-27, display overlapping, but not redundant, roles in regulating lymphocyte subpopulations. IL-12 is known as a potent antitumor cytokine, whereas the results of the antitumor effect of IL-23 and IL-27 are inconsistent. The present study aimed to directly compare the relative antitumor efficacy of these three IL-12 family cytokines on HCC. Methods: A murine orthotopic BNL HCC model, in which the tumor is located in an environment heavily populated with different lymphocyte subsets, was established. The hepatotropic adeno-associated virus serotype 8 (AAV8) vector was used to deliver the cytokine genes aiming to achieve sustained cytokine expression in the liver. Results: AAV8/IL-12 treatment significantly reduced hepatic metastases and prolonged survival time, whereas treatment with AAV8/IL-23 or AAV8/IL-27 had only moderate antitumor effects at a high dose. The antitumor efficacy of these cytokines was positively correlated with their ability to regulate hepatic T cells, natural killer cells and natural killer T cells, with IL-12 greatly increasing the number and activation status of these cells, whereas IL-27 had no effect and IL-23 had a negative effect. AAV8/IL-12 treatment also resulted in a marked decrease in tumor vessel density, which was not observed with AAV8/IL-23 and AAV8/IL-27 treatment. Conclusions: The data obtained in the present study highlight the importance of local lymphocytes and anti-angiogenesis for influencing the antitumor activity of these three IL-12 family cytokines and suggest that IL-12 is the best candidate for treating HCC.",
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AU - Chen, Yin

AU - Wu, Ping Yi

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AB - Background: Hepatocellular carcinoma (HCC) is one of the most difficult cancers to treat. The interleukin (IL)-12 family cytokines, including IL-12, IL-23 and IL-27, display overlapping, but not redundant, roles in regulating lymphocyte subpopulations. IL-12 is known as a potent antitumor cytokine, whereas the results of the antitumor effect of IL-23 and IL-27 are inconsistent. The present study aimed to directly compare the relative antitumor efficacy of these three IL-12 family cytokines on HCC. Methods: A murine orthotopic BNL HCC model, in which the tumor is located in an environment heavily populated with different lymphocyte subsets, was established. The hepatotropic adeno-associated virus serotype 8 (AAV8) vector was used to deliver the cytokine genes aiming to achieve sustained cytokine expression in the liver. Results: AAV8/IL-12 treatment significantly reduced hepatic metastases and prolonged survival time, whereas treatment with AAV8/IL-23 or AAV8/IL-27 had only moderate antitumor effects at a high dose. The antitumor efficacy of these cytokines was positively correlated with their ability to regulate hepatic T cells, natural killer cells and natural killer T cells, with IL-12 greatly increasing the number and activation status of these cells, whereas IL-27 had no effect and IL-23 had a negative effect. AAV8/IL-12 treatment also resulted in a marked decrease in tumor vessel density, which was not observed with AAV8/IL-23 and AAV8/IL-27 treatment. Conclusions: The data obtained in the present study highlight the importance of local lymphocytes and anti-angiogenesis for influencing the antitumor activity of these three IL-12 family cytokines and suggest that IL-12 is the best candidate for treating HCC.

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