Transforming growth factor-beta pathway in human renal cell carcinoma and surrounding normal-appearing renal parenchyma.
OBJECTIVE
To analyze the role of the transforming growth factor (TGF)-beta pathway in renal tumors and to verify whether alterations in TGF-beta 1 pathway expression are associated with the grade of tumor differentiation and pathologic stage in renal cell carcinomas.


METHODS
The expression of TGF-beta 1 and TGF-beta receptors (T beta RI and T beta RII), SMAD-2 and SMAD-4 was investigated by immunohistochemistry in normal peritumoral and tumoral tissue from 53 renal cell carcinomas (clear cell type). The gene expression of SMAD-2 and SMAD-4 was also studied by reverse transcription polymerase chain reaction (RT-PCR) in normal peritumoral and tumoral tissue from 6 of 56 primary tumors.


RESULTS
TGF-beta 1, T beta RI and T beta RII immunoreactivity was more frequent in tumoral than in normal peritumoral renal tissue (96.22%, 79.25% and 75.41% vs. 88.37%, 69.76% and 62.69%), whereas SMAD-2 and SMAD-4 immunoreactivity was more frequent in normal peritumoral than in tumoral tissue (23.25% and 30.23% vs. 15.09% and 7.54%). In tumor areas, immunohistochemical scores were lower for T beta RII than for T beta RI and TGF-beta 1 and higher than SMAD-4 and SMAD-2 scores. TGF-beta 1, T beta RI, T beta RII and SMAD-4 histologic scores correlated with neither the histologic grade of malignancy nor TNM clinical stage, whereas SMAD-2 protein levels were significantly lower in grade 3 than in grade 1 tumors. In the samples of normal kidney and carcinoma studied, RT-PCR detected the correct transcripts for SMAD-2 and SMAD-4, indicating that the RNA of the samples analyzed contained RNA sequences coding for these genes.


CONCLUSIONS
Our data support the concept that the reduction of T beta RII and SMAD proteins in renal cell carcinomas is involved in tumor development and suggest an altered TGF-beta/SMAD signaling pathway in kidney neoplasia.
Cardillo
M R
MR
Departments of Experimental Medicine and Pathology and of Urology, University La Sapienza, Rome, Italy.
Lazzereschi
D
D
Gandini
O
O
Di Silverio
F
F
Colletta
G
G
D002292:Carcinoma, Renal Cell / Q000378:metabolism* / Q000473:pathology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007668:Kidney / Q000378:metabolism*; D007680:Kidney Neoplasms / Q000378:metabolism* / Q000473:pathology*; D016133:Polymerase Chain Reaction; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D051899:Smad2 Protein; D051901:Smad4 Protein; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*
D004268:DNA-Binding Proteins; D018125:Receptors, Transforming Growth Factor beta; C497782:SMAD2 protein, human; C497796:SMAD4 protein, human; D051899:Smad2 Protein; D051901:Smad4 Protein; D015534:Trans-Activators; D016212:Transforming Growth Factor beta