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Effect of in vivo loss of GDF-15 on hepatocellular carcinogenesis

Journal of Cancer Research and Clinical Oncology volume 134, pages 753–759 (2008)Cite this article

Abstract

Background

Growth/differentiation factor-15(GDF-15) is a divergent TGF-β family member that is expressed following liver injury and carcinogen exposure. GDF-15 expression is highly associated with gastrointestinal cancer stage, size, and metastasis and has been implicated in inhibition of tumor growth and increased tumor invasiveness. The current study sought to determine the effect of GDF-15 ablation on the development of hepatocellular carcinoma (HCC) in vivo.

Materials and methods

Male mice genetically deleted for the gene encoding GDF-15 (Gdf15 −/− mice) and wild-type controls were exposed to the hepatocarcinogen diethylnitrosamine (DEN). Mice were killed at 6 months of age and their livers dissected and processed for histology. Tumor number and size relative to total liver area examined were determined.

Results

At 6 months of age, tumors were identified in 16 of 20 (80%) Gdf15 −/− mice and 16 of 19 wild-type mice (84%). No significant difference in tumor-occupied area was observed in Gdf15 −/− mice versus wild-type mice. In addition, no difference in invasiveness was observed in HCC arising in Gdf15 −/− as compared to wild-type mice. In wild type mice strong immunohistochemical staining for GDF-15 was noted on small HCC foci, whereas a loss of GDF-15 expression was found in a number of advanced HCC tumors.

Conclusions

Although highly expressed in association with multiple gastrointestinal cancers, and lost in some advanced HCC, genetic ablation of GDF-15 has no apparent effect on HCC tumor formation rate, growth rate or invasiveness in diethylnitrosamine-induced HCC in vivo.

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Abbreviations

HCC:

Hepatocellular carcinoma

GDF-15:

Growth/differentiation factor-15 (protein)

Gdf15 :

Growth/differentiation factor-15 (gene)

TGF β:

Transforming growth factor-β

DEN:

Diethylnitrosamine

PCNA:

Proliferating cell nuclear antigen

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Acknowledgments

The authors wish to thank Dr. Klaus Unsicker of Heidelberg, Germany for his kind gift of anti-GDF-15 antibody. This study was supported by a grant from The National Institutes of Health, GMS Grant #63603 (LGK).

Author information

Affiliations

  1. DeWitt Daughtry Family Department of Surgery and Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA

    Teresa A. Zimmers, Xiaoling Jin, Juan C. Gutierrez, Cary Acosta & Leonidas G. Koniaris

  2. Department of Biology, University of North Carolina at Charlotte, Charlotte, NC, USA

    Iain H. McKillop

  3. Department of Pathology, University of Rochester School of Medicine, Rochester, NY, USA

    Robert H. Pierce

  4. Alan Livingstone Chair in Surgical Oncology, 3550 Sylvester Comprehensive Cancer Center (310T), 1475 NW 12th Avenue, Miami, FL, 33136, USA

    Leonidas G. Koniaris

Authors
  1. Teresa A. Zimmers
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  2. Xiaoling Jin
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  3. Juan C. Gutierrez
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  4. Cary Acosta
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  5. Iain H. McKillop
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  6. Robert H. Pierce
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  7. Leonidas G. Koniaris
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Corresponding author

Correspondence to Leonidas G. Koniaris.

Additional information

Teresa A. Zimmers and Xiaoling Jin have contributed equally to this work.

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Zimmers, T.A., Jin, X., Gutierrez, J.C. et al. Effect of in vivo loss of GDF-15 on hepatocellular carcinogenesis. J Cancer Res Clin Oncol 134, 753–759 (2008). https://doi.org/10.1007/s00432-007-0336-4

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  • DOI: https://doi.org/10.1007/s00432-007-0336-4

Keywords

  • Hepatocellular carcinoma
  • Growth/differentiation factor-15
  • Transforming growth factor-β
  • Transgenic/knockout
  • hPDF
  • hPLAB
  • hPTGF-ßPL
  • hNAG-1