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

John A. Copland, Bruce A. Luxon, Laila Ajani, Tapati Maity, Erica Campagnaro, Huiping Guo, Shauna N. LeGrand, Pheroze Tamboli, Christopher G. Wood

    Research output: Contribution to journalArticle

    87 Citations (Scopus)

    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.

    Original languageEnglish
    Pages (from-to)8053-8062
    Number of pages10
    JournalOncogene
    Volume22
    Issue number39
    DOIs
    StatePublished - Sep 11 2003

    Fingerprint

    Growth Factor Receptors
    Transforming Growth Factors
    Renal Cell Carcinoma
    Carcinogenesis
    Kidney
    Cell Line
    Phenotype
    Cell Proliferation
    Health

    Keywords

    • Carcinogenesis
    • Metastasis
    • Renal cell carcinoma
    • TGFβ
    • Type II TGFβ receptor
    • Type III TGFβ receptor

    ASJC Scopus subject areas

    • Molecular Biology
    • Cancer Research
    • Genetics

    Cite this

    Genomic profiling identifies alterations in TGFβ signaling through loss of TGFβ receptor expression in human renal cell carcinogenesis and progression. / Copland, John A.; Luxon, Bruce A.; Ajani, Laila; Maity, Tapati; Campagnaro, Erica; Guo, Huiping; LeGrand, Shauna N.; Tamboli, Pheroze; Wood, Christopher G.

    In: Oncogene, Vol. 22, No. 39, 11.09.2003, p. 8053-8062.

    Research output: Contribution to journalArticle

    Copland, JA, Luxon, BA, Ajani, L, Maity, T, Campagnaro, E, Guo, H, LeGrand, SN, Tamboli, P & Wood, CG 2003, 'Genomic profiling identifies alterations in TGFβ signaling through loss of TGFβ receptor expression in human renal cell carcinogenesis and progression', Oncogene, vol. 22, no. 39, pp. 8053-8062. https://doi.org/10.1038/sj.onc.1206835
    Copland, John A. ; Luxon, Bruce A. ; Ajani, Laila ; Maity, Tapati ; Campagnaro, Erica ; Guo, Huiping ; LeGrand, Shauna N. ; Tamboli, Pheroze ; Wood, Christopher G. / Genomic profiling identifies alterations in TGFβ signaling through loss of TGFβ receptor expression in human renal cell carcinogenesis and progression. In: Oncogene. 2003 ; Vol. 22, No. 39. pp. 8053-8062.
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    AU - Maity, Tapati

    AU - Campagnaro, Erica

    AU - Guo, Huiping

    AU - LeGrand, Shauna N.

    AU - Tamboli, Pheroze

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    AB - 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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    KW - Type III TGFβ receptor

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