Involvement of transforming growth factor-alpha and its receptor in a model of DES-induced renal carcinogenesis in the Syrian hamster.
This study explores the role played by TGF alpha in estrogen-induced renal tumors. Tumors were induced in male Syrian hamster by chronic administration of diethylstilbestrol (DES). Six experimental groups (n = 5-9) were chronically exposed to DES and sacrificed after 1, 2, 4, 6, 9 and 11 months, respectively. In the course of treatment, the nephrons were the site of an important increase of cell turnover, which was characterized by a process of hyperplasia/dysplasia in proximal tubules preceding the neoplastic transformation. In treated animals and in controls, the analysis of renal tissue by Western blot revealed the presence of a 6 kDa polypeptide crossreacting with anti-TGF alpha antibody. In controls, TGF alpha immunoreactivity was localized in proximal and in distal tubules. Before tumor development (1-4 months), TGF alpha RIA showed an increase of TGF alpha concentration in renal tissue, in parallel with the increased cell proliferation observed in proximal tubules. In addition, Western blot analysis also demonstrated in kidney tissue the presence of a 165 kDa protein displaying the immunoreactivity of EGF/TGF alpha receptor. The receptor immunoreactivity was localized in proximal tubular cells suggesting an involvement of TGF alpha in tubular epithelial growth through autocrine or paracrine pathways. In large neoplasms, immunocytochemistry revealed only clusters of transformed cells intensely stained by the anti-TGF alpha antibody. These cells displayed the appearance of stellate or polyhedric cells infiltrating adjacent neoplastic tissues. Antisera raised against intra- or extracytoplasmic domains of the EGF/TGF alpha receptor were assayed to localize this receptor in the tumors. In contrast with tubular structures, immunoreactivity to EGF/TGF alpha receptor was never detected in tumoral tissue. The apparent absence of EGF/ TGF alpha receptor immunoreactivity in malignant cells seems to exclude an involvement of this growth factor in the tumorigenic process, although it could be involved in tumor neovascularization.
Wattiez
R
R
Department of Biological Chemistry, School of Sciences, University of Mons-Hainaut, Belgium.
Nonclercq
D
D
Journé
F
F
Toubeau
G
G
Zanen
J
J
Falmagne
P
P
Heuson-Stiennon
J A
JA
D000595:Amino Acid Sequence; D000818:Animals; D015153:Blotting, Western; D002273:Carcinogens / Q000633:toxicity*; D002455:Cell Division; D006224:Cricetinae; D004054:Diethylstilbestrol / Q000633:toxicity*; D066246:ErbB Receptors / Q000378:metabolism / Q000502:physiology*; D007150:Immunohistochemistry; D007680:Kidney Neoplasms / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D007687:Kidney Tubules, Proximal / Q000378:metabolism; D008297:Male; D008647:Mesocricetus; D008969:Molecular Sequence Data; D011863:Radioimmunoassay; D016211:Transforming Growth Factor alpha / Q000378:metabolism / Q000502:physiology*
D002273:Carcinogens; D016211:Transforming Growth Factor alpha; D004054:Diethylstilbestrol; D066246:ErbB Receptors