Abstract
TGFβ1 is one of several cytokines produced by proximal tubular and renal cancer cells. Previous studies have been mainly focused on determining plasma or serum TGFβ levels, its effect on RCC cultures, and the expression of TGFβ mRNA. Cancerous and autologous normal kidney samples were obtained from 24 patients treated by radical nephrectomy. TGFβ1 expression was determined using a semi quantitative Western blot analysis and immunohistochemistry. Blot densities and immunohistochemical expression intensities in normal and neoplastic tissue were compared, and subsequently correlated to tumor stage, histological type and nuclear grade. All tissue samples examined expressed TGFβ1; mean tumor to non-involved kidney spot density ratio correlated with advancing stage and higher nuclear grade. The overexpression of TGFβ1 in certain RCCs may partially explain their resistance to the growth suppression action of TGFβ. The correlation with tumor stage and grade indicates a possible role in the development of metastatic potential as well as in host’s immune response modulation.
Similar content being viewed by others
References
Atlas I, Mendelsohn J, Baselga J, Fair WR, Masui H, Kumar R (1992) Growth regulation of human renal carcinoma cells: role of transforming growth factor alpha. Cancer Res 52:3335
Border W, Noble N (1995) Targeting TGFβ for treatment of diseases. Nat Med 1:1000
Cardillo MR, Lazzereschi D, Galdini O, Di Silverio F, Colletta G (2001) Transforming growth factor-beta pathway in human renal cell carcinoma and surrounding normal-appearing renal parenchyma. Anal Quant Cytol Histol 23:109
Cerwenka A, Bevec D, Majdic O, Knapp W, Holter W (1994) TGF-beta 1 is a potent inducer of human effector T cells. J Immunol 153:4367
Chang SG, Shin C, Rho SK, Kim DK, Kim JH (1998) Cytokine production in primary histoculture by human normal kidney, renal cell carcinoma and benign renal angiomyolipoma tissues. Anticancer Res 18:4195
Derynck R, Goeddel DV, Ullrich A, Gutterman JU, Wiiliams RD, Bringman TS, Berger WH (1987) Synthesis of messenger RNAs for transforming growth factors α and β and the epidermal growth factor receptors by human tumors. Cancer Res 47:707
Filmus J, Kerbel RS (1993) Development of resistance mechanisms to the growth-inhibitory effects of transforming growth factor-beta during tumor progression. Curr Opin Oncol 5:123
Gomella LG, Sargent ER, Linehan WM, Kasid A (1989) Transforming growth factor-beta inhibits the growth of renal cell carcinoma in vitro. J Urol 141:1240
Gomella LG, Sargent ER, Wade TP, Anglard P, Linehan WM, Kasid A (1989) Expression of transforming growth factor α in normal human adult kidney and of transforming growth factors α and β1 in renal cell carcinoma. Cancer Res 49:6972
Hall S, Hsieh T-C, Ng C-Y, Mallouh C, Wu JM (1996) Control of renal carcinoma TC-1 growth, cyclin/kinase and nm23 expression by IFN-γ and TGF-β. Anticancer Res 16:1755
Hegele A, Vagra Z, Von Knobloch R, Heidenreich A, Kropf J, Hofmann R (2002) TGFβ1 in patients with renal cell carcinoma. Urol Res 30:126
Herman ME, Katzenellenbogen BS (1994) Alterations in transforming growth factor α and β production and cell responsiveness during the progression of MCF-7 human breast cancer cells to eostrogen–autonomous growth. Cancer Res 54:5876
Junker U, Knoefel B, Rebstock K, Steiner T, Wunderlich H, Junker K, Reinhold D (1996) Transforming growth factor beta 1 is significantly elevated in plasma of patients suffering from renal cell carcinoma. Cytokine 8:794
Junker U, Haufe CC, Nuske K, Rebstock K, Steiner T, Wunderlich H, Junker K, Reinhold D (2000) Elevated plasma TGFbeta1 in renal diseases: cause or consequence ? Cytokine 12:1084
Kerbel RS (1992) Expression of multi-cytokine resistance and multi-growth factor independence in advanced stage metastatic cancer. Malignant melanoma as a paradigm. Am J Pathol 141:519
Knoefel B, Nuske K, Steiner T, Junker K, Kosmehl H, Rebstock K, Reinhold D, Junker U (1997) Renal cell carcinomas produce IL-6, IL-10, IL-11 and TGF beta-1 in primary cultures and modulate T-lymphocyte blast formation. J Interferon Cytokine Res 17:95
Kundu SD, Kim IY, Zelner D, Janulis L, Goodwin S, Engel JD, Lee C (1998) Absence of expression of transforming growth factor-beta type II receptor is associated with an aggressive growth pattern in a murine renal cell carcinoma cell line, Renca. J Urol 160:1883
Laemli UK (1970) Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 227:680
Landis SH, Murray T, Bolden S, Wingo PA (1999) Cancer statistics 1999. CA Cancer J Clin 49:8
Lyons RM, Moses HL (1990) Transforming growth factors and the regulation of cell proliferation. Eur J Biochem 187:467
Maniatis T, Fritch EF and Sambrook KJ (1982) Detection and Analysis of proteins expressed from cloned genes. In: Maniatis T, Fritch EF, Sambrook KJ (eds) Molecular cloning: a laboratory manual. Cold Spring Harbor, New York, p 18.47
Maniatis T, Fritsch EF, Sambrook KJ (1982) Detection and analysis of proteins expressed from cloned genes. In: Maniatis T, Fritch EF, Sambrook KJ (eds) Molecular cloning: a laboratory manual. Cold Spring Harbor, New York, p 18.60
Markowitz SD, Roberts AB (1996) Tumor suppressor activity of the TGFβ pathway in human cancers. Cytokine Growth Factor Rev 7:93
Massague J (1990) The transforming growth factor β family. Annu Rev Cell Biol 6:597
Michel K, Tso CL, Mulders P, Kernion JD, Beldegrun A (1997) Expression of TGFβ1 in renal cell carcinoma (RCC); putative role of TGFβ as tumor infiltrating lymphocyte (TIL) suppressor. J Urol 157 [Suppl]:376
Miyazono K, Ichijo H and Heldin CH (1993) Transforming growth factor β: Latent forms, binding proteins and receptors. Growth Factors 8:11
Mulder KM, Ramey MR, Hoosen NM, Levine AE, Hinshaw XH, Brattain DE, Brattain MG (1988) Characterization of transforming growth factor-beta-resistant subclones isolated from a transforming growth factor-beta-sensitive human colon carcinoma cell line. Cancer Res 48:7120
Olive C, Cheung C, Nicol D, Falk MC (1998) Expression of cytokine mRNA transcripts in renal cell carcinoma. Immunol Cell Biol 76:357
Phillips AO, Steadman R, Topley N, Williams JD (1995) Elevated D-glucose concentrations modulate TGF-beta1 synthesis by human cultured renal proximal tubular cells .The permissive role of platelet-derived growth factor. Am J Pathol 147:362
Polyak K (1996) Negative regulation of cell growth by TGF beta. Biochim Biophys Acta 1242:185
Ramp U, Jaquet K, Reinecke P, Nitsch T, Gabbert HE, Gerharz CD (1997) Acquisition of TGF-beta 1 resistance: an important progression factor in human renal cell carcinoma. Lab Invest 76:739
Roberts AB, Sporn MB, Assoian RK, Smith JM, Roche WS, Wakefield LA, Heine UI, Liotta LA, Falanga V, Kehl JH, Fauci AS (1986) Transforming growth factor β: rapid induction of fibrosis and angiogenesis in vivo and stimulation of collagen formation in vitro. Proc Natl Acad Sci U S A 83:4167
Sankar S, Mahooti–Brooks N, Bensen L, McCarthy TL, Centrella M, Madri JA (1996) Modulation of transforming growth factor beta receptor levels on microvascular endothelial cells during in vitro angiogenesis. J Clin Invest 97:1436
Sene AP, Hunt L, McMahon RF, Carroll RN (1992) Renal carcinoma in patients undergoing nephrectomy: analysis of survival and prognostic factors. Br J Urol 70:125
Smith PK, Krohn RI, Hermanson GT, Mallia AK, Gartner FH, Provenzano MD, Fujimoto EK, Gocke NM, Olson BJ, Klenk DC (1985) Measurement of protein using bicinchoninic acid. Anal Biochem 150:76
Storkel S, Eble J, Adlakha K, Amin M, Blute ML, Bostwick DG, Darson M, Delahunt B, Iczkowski K (1997) Classification of renal cell carcinoma: Workgroup No1, Union Internationale Contre le Cancer (UICC) and the American Joint Committee on Cancer (AJCC). Cancer 80:987
Towbin H, Staehelin T, Gordon J (1979) Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets: procedure and some applications. Proc Natl Acad Sci U S A 76:4350
Van Brussel JP, Mickisch GH (1999) Prognostic factors in renal cell and bladder cancer. BJU Int 83:902
Wechsel HW, Bichler KH, Feil G, Loeser W, Lahme S, Petri E (1999) Renal cell carcinoma: relevance of angiogenetic factors. Anticancer Res 19:1537
Wunderlich H, Steiner T, Junker U, Knoefel B, Schlichter A, Schubert J (1996) Serum transforming growth factor β1 in patients with renal cell carcinoma. J Urol 157:1602
Wunderlich H, Steiner T, Kosmehl H, Junker U, Reinhold D, Reichelt O, Zermann DH, Schubert J (1998) Increased transforming growth factor beta 1 plasma level in patients with renal cell carcinoma: a tumor-specific marker? Urol Int 60:205
Acknowledgements
The authors acknowledge the skillful technical contribution of Penelope Chiara (medical arts), Despina Karandrea and Vasiliki Dotsika.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Mitropoulos, D., Kiroudi, A., Christelli, E. et al. Expression of transforming growth factor β in renal cell carcinoma and matched non-involved renal tissue. Urol Res 32, 317–322 (2004). https://doi.org/10.1007/s00240-003-0360-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00240-003-0360-z