Abstract
A high incidence of renal adenocarcinoma has been observed in rats treated with ferric nitrilotriacetate (Fe‐NTA) but not in rats treated with aluminum nitrilotriacetate (Al‐NTA). Transforming growth factor (TGF)‐α is one of the several cytokines that is known to be expressed in human and rat renal adenocarcinomas. However, its role in neoplastic transformation is still questionable. Therefore, we investigated the effect of repeated Fe‐NTA and Al‐NTA administration on renal TGF‐α expression. Male Wistar rats were given Fe‐NTA (n = 16, 5–10 mg FeAg) and Al‐NTA (n = 19, 1–2 mg Al/kg) i.p., three times a week for 3 or 12 weeks. Another group of rats (n=4) was given Fe‐NTA (5–10 mg FeAg) three times a week for 12 weeks and then left untreated for one year. Immunoreactivity for TGF‐α was positive in the collecting ducts and on the apical surface of proximal tubules in the outer stripe of the outer medulla in all the animals including NTA‐injected control animals. However, TGF‐α immunoreactivity in the regenerative proximal tubular epithelium was observed only in the animals treated with Fe‐NTA for 12 weeks. Northern blot analysis also showed expression of TGF‐α mRNA only in animals treated with Fe‐NTA for 12 weeks. The expression of TGF‐α mRNA in the kidney was stronger than that in the liver or brain, TGF‐α was also positive in renal cell carcinoma found in animals treated with Fe‐NTA for 12 weeks and left untreated for one year. These results suggest that TGF‐α expression may play an important role in renal carcinogenesis and that it may be a sensitive marker during the induction stage of renal cell carcinoma.
Keywords: TGF‐α, Renal cell carcinoma, Carcinogenesis, Ferric nitrilotriacetate, Aluminum nitrilotriacetate
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REFERENCES
- 1. ) Sugawara , K. , Sugawara , I. , Sukegawa , J. , Akatsuka , T. , Yamamoto , T. , Morita , M. , Mori , S. and Toyoshima , K.Distribution of c‐yes‐l gene product in various cells and tissues . Br. J. Cancer , 63 , 508 – 513 ( 1991. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2. ) Sakai , N. , Shuin , T. and Hosaka , M.Enhanced expression of A‐myb and B‐myb genes in primary human renal cell carcinoma . Proc. Am. Assoc. Cancer Res. , 32 , 19 ( 1991. ). [Google Scholar]
- 3. ) Maehle , L. , Metcalf , R. , Ryberg , D. , Bennet , W. P. , Harris , C. C. and Haugen , A.Altered p53 gene structure and expression in a human renal epithelial multistep model of in vitro carcinogenesis . Proc. Am. Assoc. Cancer Res. , 32 , 140 ( 1991. ). [Google Scholar]
- 4. ) Kinouchi . T. , Saiki , S. , Naoe , T. , Uenaka , A. , Kotake , T. , Shiku , H. and Nakayama , E.Correlation of c‐myc expression with nuclear pleomorphism in human renal cell carci‐ noma . Cancer Res. , 49 , 3627 – 3630 ( 1989. ). [PubMed] [Google Scholar]
- 5. ) Petrides , P. E. , Bock , S. , Bovens , J. , Hofmann , R. and Jakse , G.Modulation of pro‐epidermal growth factor, protransforming growth factor α and epidermal growth factor receptor gene expression in human renal carcinomas . Cancer Res. , 50 , 3934 – 3939 ( 1990. ). [PubMed] [Google Scholar]
- 6. ) Walker , C. , Everitt , J. , Freed , J. J. , Knudson , A. G. , Jr. and Whiteley , L. O.Altered expression of transforming growth factor‐α in hereditary rat renal cell carcinoma . Cancer Res. , 51 , 2973 – 2978 ( 1991. ). [PubMed] [Google Scholar]
- 7. ) Sargent , E. R. , Gomella , L. G. , Belldegrun , A. , Linehan , W. M. and Kasid , A.Epidermal growth factor receptor gene expression in normal human kidney and renal cell carcinoma . J. Urol. , 142 , 1364 – 1368 ( 1989. ). [DOI] [PubMed] [Google Scholar]
- 8. ) Freeman , M. R. , Washecka , R. and Chung , L. W. K.Aberrant expression of epidermal growth factor receptor and HER‐2 (erbB‐2) messenger RNAs in human renal cancers . Cancer Res. , 49 , 6221 – 6225 ( 1989. ). [PubMed] [Google Scholar]
- 9. ) Yao , M. , Shuin , T. , Misaki , H. and Kubota , Y.Enhanced expression of c‐myc and epidermal growth factor receptor (c‐erbB‐1) genes in primary human renal cancer . Cancer Res. , 48 , 6753 – 6757 ( 1988. ). [PubMed] [Google Scholar]
- 10. ) Weidner , U. , Peter , S. , Strohmeyer , T. , Hussnαtter , R. , Ackermann , R. and Sies , H.Inverse relationship of epidermal growth factor receptor and HER2/neu gene expression in human renal cell carcinoma . Cancer Res. , 50 , 4504 – 4509 ( 1990. ). [PubMed] [Google Scholar]
- 11. ) Mydlo , J. H. , Michaeli , J. , Cordon‐Cardo , C. , Goldenberg , A. S. , Heston , W. D. W. and Fair , W. R.Expression of transforming growth factor α and epidermal growth factor receptor messenger RNA in neoplastic and nonneoplastic human kidney tissue . Cancer Res. , 49 , 3407 – 3411 ( 1989. ). [PubMed] [Google Scholar]
- 12. ) Atlas , I. , Mendelsohn , J. , Baselga , J. , Fair , W. R. , Masui , H. and Kumar , R.Growth regulation of human renal carcinoma cells: role of transforming growth factor α . Cancer Res. , 52 , 3335 – 3339 ( 1992. ). [PubMed] [Google Scholar]
- 13. ) Ebina , Y. , Okada , S. , Hamazaki , S. , Ogino , F. , Li , J‐L. , and Midorikawa , O.Nephrotoxicity and renal cell carcinoma after use of iron‐ and aluminum‐nitrilotriacetate complexes in rats . J. Natl. Cancer Inst. , 76 , 107 – 113 ( 1986. ). [PubMed] [Google Scholar]
- 14. ) Li , J‐L. , Okada , S. , Hamazaki , S. , Ebina , Y. and Midorikawa , O.Subacute nephrotoxicity and induction of renal cell carcinoma in mice treated with ferric nitrilotriacetate . Cancer Res. , 47 , 1867 – 1869 ( 1987. ). [PubMed] [Google Scholar]
- 15. ) Ebina , Y. , Okada , S. , Hamazaki , S. and Midorikawa , O.Liver, kidney, and central nervous system toxicity of aluminum given intraperitoneally to rats: a multiple‐dose sub‐chronic study using aluminum nitrilotriacetate . Toxicol. Appl. Pharmacol. , 75 , 211 – 218 ( 1984. ). [DOI] [PubMed] [Google Scholar]
- 16. ) Awai , M. , Narasaki , M. , Yamanoi , Y. and Seno , S.Induction of diabetes in animals by parenteral administration of ferric nitrilotriacetate: a model of experimental hemochromatosis . Am. J. Pathol. , 95 , 663 – 674 ( 1979. ). [PMC free article] [PubMed] [Google Scholar]
- 17. ) Chomczynski , P. and Sacchi , N.Single‐step method of RNA isolation by acid guanidinium thiocyanate‐phenol‐chloroform extraction . Anal. Biochem. , 162 , 156 – 159 ( 1987. ). [DOI] [PubMed] [Google Scholar]
- 18. ) Sambrook , J. , Fritsch , E. F. and Maniatis , T. “ Molecular Cloning. A Laboratory Manual ,” 2nd Ed. ( 1989. ). Cold Spring Harbor Laboratory; , Cold Spring Harbor , NY . [Google Scholar]
- 19. ) McGeady , M. L. , Kerby , S. , Shankar , V. , Ciardiello , F. , Salomon , D. and Seidman , M.Infection with a TGF‐α retroviral vector transforms normal mouse mammary epithelial cells but not normal rat fibroblasts . Oncogene , 4 , 1375 – 1382 ( 1989. ). [PubMed] [Google Scholar]
- 20. ) Jhappan , C. , Stahle , C. , Harkins , R. N. , Fausto , N. , Smith , G. H. and Merlino , G. T.TGF‐α overexpression in transgenic mice induces liver neoplasia and abnormal development of the mammary gland and pancreas . Cell , 61 , 1137 – 1146 ( 1990. ). [DOI] [PubMed] [Google Scholar]
- 21. ) Matsui , Y. , Halter , S. A. , Holt , J. T. , Hogan , B. L. M. and Coffey , R. J.Development of mammary hyperplasia and neoplasia in MMTV‐TGFα transgenic mice . Cell , 61 , 1147 – 1155 ( 1990. ). [DOI] [PubMed] [Google Scholar]
- 22. ) Hard , G. C.Experimental models for the sequential analysis of chemically‐induced renal carcinogenesis . Toxicol. Pathol. , 14 , 112 – 122 ( 1986. ). [DOI] [PubMed] [Google Scholar]
- 23. ) Cohen , A. J. , Li , F. P. , Berg , S. , Marchetto , D. J. , Tsai , S. , Jacobs , S. C. and Brown , R. S.Hereditary renal‐cell carcinoma associated with a chromosomal translocation . N. Engl. J. Med. , 301 , 592 – 595 ( 1979. ). [DOI] [PubMed] [Google Scholar]
- 24. ) Yoshida , M. A. , Ohyashiki , K. , Ochi , H. , Gibas , Z. , Pontes , J. E. , Prout , G. R.Jr. , , Huben , R. and Sandberg , A. A.Cytogenetic studies of tumor tissue from patients with nonfamilial renal cell carcinoma . Cancer Res. , 46 , 2139 – 2147 ( 1986. ). [PubMed] [Google Scholar]
- 25. ) Zbar , B. , Brauch , H. , Talmadge , C. and Linehan , M.Loss of alleles of loci on the short arm of chromosome 3 in renal cell carcinoma . Nature , 327 , 721 – 724 ( 1987. ). [DOI] [PubMed] [Google Scholar]
- 26. ) Kovacs , G. , Erlandsson , R. , Boldog , F. , Ingvarsson , S. , Müller‐Brechlin , R. , Klein , G. and Sümegi , J.Consistent chromosome 3p deletion and loss of heterozygosity in renal cell carcinoma . Proc. Natl. Acad. Sci. USA , 85 , 1571 – 1575 ( 1988. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27. ) Yoshida , M. A. , Ikeuchi , T. , Tachibana , Y. , Takagi , K. , Moriyama , M. and Tonomura , A.Rearrangements of chromosome 3 in nonfamilial renal cell carcinomas from Japanese patients . Jpn. J. Cancer Res. , 79 , 600 – 607 ( 1988. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28. ) Yamakawa , K. , Morita , R. , Takahashi , E. , Hon , T. , Ishikawa , J. and Nakamura , Y.A detailed deletion mapping of the short arm of chromosome 3 in sporadic renal cell carcinoma . Cancer Res. , 51 , 4707 – 4711 ( 1991. ). [PubMed] [Google Scholar]
- 29. ) Funaki , K. , Everitt , J. , Oshimura , M. , Freed , J. J. , Knudson , A. G. , Jr. and Walker , C.Hereditary renal cell carcinoma in the rat associated with nonrandom loss of chromosomes 5 and 6 . Cancer Res. , 51 , 4415 – 4422 ( 1991. ). [PubMed] [Google Scholar]
- 30. ) Funaki , K. , Oshimura , M. and Walker , C.Chromosome alterations in rat kidney epithelial cells transformed with MNNG . Proc. Jpn. Cancer Assoc., 51st Annu. Meet. , 115 ( 1992. ) ( in Japanese ). [Google Scholar]