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Silencing of TLR4 Decreases Liver Tumor Burden in a Murine Model of Colorectal Metastasis and Hepatic Steatosis

  • Laboratory and Translational Research
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Abstract

Background

The relationship between obesity and cancer has become of particular interest due to the rapidly growing prevalence of overweight individuals. Obesity predisposes individuals to the development of hepatic steatosis and is an independent risk factor for several neoplasms. Toll-like receptor 4 (TLR4) is the innate receptor for endotoxin, and steatotic livers are known to be sensitive to endotoxin. TLR4 signaling has been shown to have proneoplastic effects in vitro due to its effect on immune surveillance. Thus far, studies have predominantly focused on the effect of tumor-cell-derived TLR4 without regard to host TLR4 signaling.

Results

In the present study we show that steatotic livers have increased expression of TLR4. Obese animals developed higher metastatic tumor burden in the liver than lean controls regardless of the presence or absence of intact host TLR4. After silencing TLR4 expression using RNAi in the mouse colon cancer cell line MC38, there was a significant decrease in metastatic tumor burden within the liver of obese animals.

Conclusions

These findings demonstrate that steatotic livers have increased susceptibility to metastatic tumor growth and that silencing tumor cell TLR4 reduces metastatic tumor burden in steatotic liver.

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Acknowledgments

Support for this work was provided by the National Institutes of Health F32 DK072976 (TME) and R01 DK61768-01 (RSC).

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Authors and Affiliations

  1. Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Vanderbilt University School of Medicine, Nashville, TN, 37232-4753, USA

    T. M. Earl MD, I. B. Nicoud PhD, J. M. Pierce BA, J. P. Wright, N. E. Majoras BA, J. E. Rubin BA, K. P. Pierre MD, D. L. Gorden MD & R. S. Chari MD, MBA

  2. Vanderbilt University Medical Center, Nashville, TN, 37232-4753, USA

    R. S. Chari MD, MBA

Authors
  1. T. M. Earl MD
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  2. I. B. Nicoud PhD
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  3. J. M. Pierce BA
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  4. J. P. Wright
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  5. N. E. Majoras BA
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  6. J. E. Rubin BA
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  7. K. P. Pierre MD
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  8. D. L. Gorden MD
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  9. R. S. Chari MD, MBA
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Corresponding author

Correspondence to R. S. Chari MD, MBA.

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Earl, T.M., Nicoud, I.B., Pierce, J.M. et al. Silencing of TLR4 Decreases Liver Tumor Burden in a Murine Model of Colorectal Metastasis and Hepatic Steatosis. Ann Surg Oncol 16, 1043–1050 (2009). https://doi.org/10.1245/s10434-009-0325-8

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  • DOI: https://doi.org/10.1245/s10434-009-0325-8

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