Abstract
To confirm our recent finding that epidermal growth factor (EGF) appeared to contribute to the tumor‐enhancing effect demonstrated by normal rat urine, we conducted 2 experiments using our heterotopically transplanted rat urinary bladder model. In experiment 1, after a single dose (0.25 mg) of N‐methyl‐N‐nitrosourea (MNU), we intravesically administered EGF (0.5 ml of 500 ng/ml phosphate‐buffered saline) once a week for 30 weeks. Instillation of EGF induced a significantly larger number of tumors than did instillation of the vehicle (P=0.03). EGF without MNU initiation did not induce tumors. In experiment 2, 2 groups received instillation of killed Escherichia coli (5 × 108 cells)/0.5 ml phosphate‐buffered saline once a week for 4 weeks to expand the MNU‐initiated cell population. Subsequent EGF treatment significantly increased the incidence of tumors (P=0.01). In the groups which did not receive killed E. coli, EGF treatment induced a significantly higher number of tumors than did vehicle treatment (P<0.001). All of the tumors were low‐grade, superficial transitional cell carcinomas. These observations indicate that EGF acts as a growth‐stimulating factor on dormant neoplastic cells and thereby increases the number of tumors.
Keywords: Epidermal growth factor, Bladder tumor, Growth stimulation, N‐Methyl‐N‐nitrosourea
Full Text
The Full Text of this article is available as a PDF (361.8 KB).
REFERENCES
- 1).Greene , L. F. , Hanash , K. M. and Farrow , G. M.Benign papilloma or papillary transitional cell carcinoma of the bladder . J. Urol. , 100 , 205 – 207 ( 1973. ). [DOI] [PubMed] [Google Scholar]
- 2).Oyasu , R. , Hirao , Y. and Izumi , K.Enhancement by urine of urinary bladder carcinogenesis . Cancer Res. , 41 , 478 – 481 ( 1981. ). [PubMed] [Google Scholar]
- 3).Momose , H. , Kakinuma , H. , Shariff , S. Y. , Mitchell , G. B. , Rademaker , A. and Oyasu , R.Tumor‐promoting effect of urinary epidermal growth factor in rat urinary bladder carcinogenesis . Cancer Res. , 51 , 5487 – 5490 ( 1991. ). [PubMed] [Google Scholar]
- 4).Yura , Y. , Hayashi , O. , Kelly , M. and Oyasu , R.Identification of epidermal growth factor as a component of rat urinary bladder tumor‐enhancing urinary fraction . Cancer Res. , 49 , 1548 – 1553 ( 1989. ). [PubMed] [Google Scholar]
- 5).Kawamata , H. , Azuma , M. , Kameyama , S. , Nan , L. and Oyasu , R.Effect of epidermal growth factor/transforming growth factor α and transforming growth factor β1 on growth in vitro of rat urinary bladder carcinoma cells . Cell Growth Differ. , 3 , 819 – 825 ( 1992. ). [PubMed] [Google Scholar]
- 6).Kawamata , H. , Kameyama , S. , Nan , L. , Kawai , K. and Oyasu , R.Effect of epidermal growth factor and transforming growth factor β1 on growth and invasive potentials of newly established rat bladder carcinoma cell line . Int. J. Cancer , 55 , 968 – 973 ( 1993. ). [DOI] [PubMed] [Google Scholar]
- 7).Kawamata , H. , Kameyama , S. and Oyasu , R.In vitro and in vivo acceleration of the neoplastic phenotype of lowtumorigenicity rat bladder carcinoma cell line by transfecting transforming growth factor‐α . Mol. Carcinog. , 9 , 210 – 219 ( 1994. ). [DOI] [PubMed] [Google Scholar]
- 8).Yamamoto , M. , Wu , H. H. , Momose , H. , Rademaker , A. and Oyasu , R.Marked enhancement of rat urinary bladder carcinogenesis by heat‐killed Escherichia coli . Cancer Res. , 52 , 5329 – 5333 ( 1992. ). [PubMed] [Google Scholar]
- 9).Kawai , K. , Yamamoto , M. , Kameyama , S. , Kawamata , H. , Rademaker , A. and Oyasu , R.Enhancement of rat urinary bladder tumorigenesis by lipopolysaccharide‐induced inflammation . Cancer Res. , 53 , 5172 – 5175 ( 1993. ). [PubMed] [Google Scholar]
- 10).Oyasu , R. , Samma , S. , Ozono , S. , Bauer , K. , Wallemark , C. B. and Homma , Y.Induction of high‐grade, high‐stage carcinomas in the rat urinary bladder . Cancer , 59 , 451 – 458 ( 1987. ). [DOI] [PubMed] [Google Scholar]
- 11).Gregory , H. , Holmes , J. E. and Wilshire , I. R.Urogastrone levels in the urine of normal adult humans . J. Clin. Endocrinol. Metab. , 45 , 668 – 672 ( 1977. ). [DOI] [PubMed] [Google Scholar]
- 12).Messing , E. M.Clinical implications of the expression of epidermal growth factor receptors in human transitional cell carcinoma . Cancer Res. , 50 , 2530 – 2537 ( 1990. ). [PubMed] [Google Scholar]
- 13).Neal , D. , Marsh , C. , Bennett , M. K. , Abel , P. D. , Hall , R. R. , Sainsbury , J. R. C. and Harris , A. L.Epidermal growth factor receptors in human bladder cancer: comparison of invasive and superficial tumors . Lancet , i , 366 – 368 ( 1985. ). [DOI] [PubMed] [Google Scholar]
- 14).Messing , E. M. and Reznikoff , C. A.Epidermal growth factor and its receptor: markers of — and targets for — chemoprevention of bladder cancer . J. Cell Biochem. Suppl. , 16I , 56 – 62 ( 1992. ). [DOI] [PubMed] [Google Scholar]
- 15).Cox , R. and Irving , C. C.Effect of N‐methyl‐N‐nitrosourea on the DNA of rat bladder epithelium . Cancer Res. , 36 , 4114 – 4118 ( 1976. ). [PubMed] [Google Scholar]
- 16).Kadlubar , F. F. , Beranek , D. T. , Wei , C. C. , Evans , F. E. , Cox , R. and Irving , C. C.Characterization of the purine ring‐opened 7‐methylguanine and its persistence in rat bladder epithelial DNA after treatment with the carcinogen N‐methylnitrosourea . Carcinogenesis , 5 , 587 – 592 ( 1984. ). [DOI] [PubMed] [Google Scholar]
- 17).Kawai , K. , Kawamata , H. , Kameyama , S. , Rademaker , A. and Oyasu , R.Persistence of carcinogen‐altered cell population in rat urothelium which can be promoted to tumors by chronic inflammatory stimuli . Cancer Res. , 54 , 2630 – 2632 ( 1994. ). [PubMed] [Google Scholar]