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  • Oncogenomics
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Genomic profiling identifies alterations in TGFβ signaling through loss of TGFβ receptor expression in human renal cell carcinogenesis and progression

Oncogene volume 22, pages 8053–8062 (2003)Cite this article

Abstract

Renal cell carcinoma (RCC) is a major health issue. Whereas localized disease can be cured surgically, there is no effective therapy for metastatic disease. The development of an effective therapy will require an understanding of the pathways that are important in RCC carcinogenesis and progression. Using genomic profiling of patient-matched tissue, we have identified aberrations in the transforming growth factor β (TGFβ) signaling pathway in RCC. We observed loss of type III TGFβ receptor (TBR3) expression in all RCC samples. This suggests that TBR3 loss is an early event in RCC carcinogenesis and plays a sentinel role in the acquisition of a tumorigenic phenotype. We also observed subsequent loss of type II TGFβ receptor (TBR2) expression in metastatic RCCs. We propose that loss of TBR3 is necessary for RCC carcinogenesis, and that loss of TBR2 leads to acquisition of a metastatic phenotype. To this end, we have identified a human renal cell carcinoma line (UMRC6) that is representative of localized, nonmetastatic RCC, reflecting a loss of TBR3, but not TBR2 expression. Another cell line, UMRC3, is highly metastatic, having lost TBR3 and TBR2 expression. We demonstrate functional loss of TGFβ responsiveness in these cell lines as observed through phenotypic and transcriptional responsiveness to exogenous TGFβ. Restoring TBR2 and TBR3 expression in UMRC3 cells attenuates cell proliferation, completely restores TGFβ-mediated transcriptional responses, and completely blocks anchorage independent-growth: while restoration of TBR2 partially restores TGFβ-mediated signaling. Based on these data, we propose that dysregulation in TGFβ signaling, through stepwise loss in receptor expression, plays a prominent role in RCC carcinogenesis and progression. In addition, these studies unequivocably demonstrate a link between loss of TBR3 and a human disease.

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Accession codes

Accessions

GenBank/EMBL/DDBJ

Abbreviations

RCC:

renal cell carcinoma

TGFβ:

transforming growth factor β

TBR3:

type III TGFβ receptor

TBR2:

type II TGFβ receptor

TBR1:

type I TGFβ receptor

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Acknowledgements

Editorial comments from Drs Aubrey Thompson and Alan Fields were invaluable in the preparation of this manuscript. This work was supported in part by the John Sealy Memorial Endowment Fund for Biomedical Research Grant#2529-01 (JAC), the American Cancer Society Grant#1003-00 (JAC), and UTMB Tobacco Funds (BAL), HRH Prince Abdulaziz bin Abdullah and his children, HRH Prince Abdullah bin Abdulaziz bin Abdullah, Prince Khalid Abdulaziz bin Abdullah and Princess Sadeen bin Abdulaziz Renal Cancer Research Fund (CGW) and Eleanor and Joseph Zuber Research Fund (CGW).

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Authors and Affiliations

  1. Endocrinology Division, Internal Medicine Department, University of Texas Medical Branch, Galveston, 77555, TX, USA

    John A Copland, Erica Campagnaro & Shauna N LeGrand

  2. Bioinformatics Program, University of Texas Medical Branch, Galveston, 77555, TX, USA

    Bruce A Luxon

  3. Department of Urology and Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, 77030, TX, USA

    Laila Ajani, Tapati Maity & Christopher G Wood

  4. Sealy Center for Cancer Cell Biology, University of Texas Medical Branch, Galveston, 77555, TX, USA

    Huiping Guo

  5. Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, 77030, TX, USA

    Pheroze Tamboli

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  1. John A Copland
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Correspondence to Christopher G Wood.

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Copland, J., Luxon, B., Ajani, L. et al. Genomic profiling identifies alterations in TGFβ signaling through loss of TGFβ receptor expression in human renal cell carcinogenesis and progression. Oncogene 22, 8053–8062 (2003). https://doi.org/10.1038/sj.onc.1206835

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