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  • Oncogenomics
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Lung adenocarcinoma invasion in TGFβRII-deficient cells is mediated by CCL5/RANTES

Oncogene volume 27, pages 557–564 (2008)Cite this article

Abstract

Recently, we identified a lung adenocarcinoma signature that segregated tumors into three clades distinguished by histological invasiveness. Among the genes differentially expressed was the type II transforming growth factor-β receptor (TGFβRII), which was lower in adenocarcinoma mixed subtype and solid invasive subtype tumors compared with bronchioloalveolar carcinoma. We used a tumor cell invasion system to identify the chemokine CCL5 (RANTES, regulated on activation, normal T-cell expressed and presumably secreted) as a potential downstream mediator of TGF-β signaling important for lung adenocarcinoma invasion. We specifically hypothesized that RANTES is required for lung cancer invasion and progression in TGFβRII-repressed cells. We examined invasion in TGFβRII-deficient cells treated with two inhibitors of RANTES activity, Met-RANTES and a CCR5 receptor-blocking antibody. Both treatments blocked invasion induced by TGFβRII knockdown. In addition, we examined the clinical relevance of the RANTES–CCR5 pathway by establishing an association of RANTES and CCR5 immunostaining with invasion and outcome in human lung adenocarcinoma specimens. Moderate or high expression of both RANTES and CCR5 was associated with an increased risk for death, P=0.014 and 0.002, respectively. In conclusion, our studies indicate RANTES signaling is required for invasion in TGFβRII-deficient cells and suggest a role for CCR5 inhibition in lung adenocarcinoma prevention and treatment.

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Acknowledgements

This work was supported in part by NIH (1RO1CA120174), American Cancer Society (RSG0524801CNE), Joan's Legacy Foundation and Flight Attendants Medical Research Institute.

We thank Dr Samuel Silverstein and Dr Yens Huseman, Department of Physiology, Columbia University College of Physicians and Surgeons, New York, NY, USA for assistance and advice.

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Authors and Affiliations

  1. Department of Pathology, Columbia University College of Physicians and Surgeons, New York, NY, USA

    A C Borczuk

  2. Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY, USA

    N Papanikolaou, R L Toonkel, M Sole & C A Powell

  3. Department of Surgery, Columbia University College of Physicians and Surgeons, New York, NY, USA

    L A Gorenstein, M E Ginsburg & J R Sonett

  4. Department of Biomedical Informatics, Columbia University College of Physicians and Surgeons, New York, NY, USA

    R A Friedman

  5. Herbert Irving Comprehensive Cancer Center, Columbia University College of Physicians and Surgeons, New York, NY, USA

    R A Friedman & C A Powell

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  1. A C Borczuk
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  2. N Papanikolaou
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  3. R L Toonkel
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  4. M Sole
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  8. R A Friedman
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  9. C A Powell
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Corresponding author

Correspondence to C A Powell.

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Supplementary information accompanies the paper on the Oncogene web site (http://www.nature.com/onc).

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Borczuk, A., Papanikolaou, N., Toonkel, R. et al. Lung adenocarcinoma invasion in TGFβRII-deficient cells is mediated by CCL5/RANTES. Oncogene 27, 557–564 (2008). https://doi.org/10.1038/sj.onc.1210662

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