Reduced expression of retinoblastoma (Rb) gene protein is related to cell proliferation and prognosis in transitional-cell bladder cancer

Journal of Cancer Research and Clinical Oncology - Tập 121 - Trang 44-50 - 1995
Pertti K. Lipponen1, Tapani J. O. Liukkonen2
1Department of Pathology, University of Kuopio Kuopio, Finland
2Department of Surgery, Mikkeli Central Hospital, Mikkeli, Finland

Tóm tắt

Archival biopsy specimens from transitional-cell bladder cancers (n=222) were analysed immunohistochemically for expression of retinoblastoma (Rb) gene protein. The intensity of staining for Rb protein and the fraction of positive nuclei were analysed and related to several other prognostic factors and survival. Six per cent of the tumours were totally negative for Rb protein and abnormal (weak) expression was found in 40% of cases. The fraction of positive nuclei and abnormal expression (weak) were highly significantly interrelated (P<0.0001). A low value for the fraction of Rb-protein-positive nuclei was related to a large fraction in S phase (P=0.001), high mitotic index (P=0.016) and overexpression of epidermal growth factor receptor (P=0.034) and p53 protein (P=0.019). A normal Rb protein expression pattern was related to low S-phase values (P=0.0001) whereas over-expression of p53 was related to high S-phase values (P=0.0077). Morphometrically measured nuclear atypia and the fraction of Rb-protein-positive nuclei were negatively correlated (P<0.05). In univariate survival analysis altered expression of Rb protein (P=0.07) and low frequency (≤50%) of Rb-protein-positive nuclei (P=0.0128) predicted a poor outcome. In a multivariate analysis, reduced expression of Rb protein had no independent prognostic value over T category, papillary status and the size of the S-phase fraction. The results show that tumour-suppressor genes Rb and p53 participate in the growth regulation of human bladder cancer cells in vivo and accordingly modify the prognosis.

Tài liệu tham khảo

Baker SJ, Markowitz S, Fearon ER, Willson JKV, Vogelstein B (1990) Suppression of human colorectal carcinoma cell growth by wildtype p53. Science 249:912–915

Banerjee A, Xu HJ, Hu SX, Araujo D, Takahashi R, Stanbridge EJ, Benedict WF (1992) Changes in growth and tumorigeneity following reconstruction of retinoblastoma gene function in various human cancer cell types by microcell transfer of chromosome 13. Cancer Res 52:6297–6304

Berger MS, Greenfield C, Gullick WJ, Haley J, Downward J, Neal DE, Harris AL, Waterfield MD (1987) Evaluation of epidermal growth factor receptors in bladder tumors. Br J Cancer 56:533–537

Bookstein R, Lee WH (1991) Molecular genetics of the retinoblastoma suppressor gene. Crit Rev Oncol 2:211–227

Bookstein R, Rio P, Madreperla SA, Hong F, Allred C, Grizzle WE, Lee W-H (1988) Promoter deletion and loss of retinoblastoma gene expression in human prostate carcinoma. Proc Natl Acad Sci USA 87:7762–7766

Buchkovich K, Duffy LA, Harlow E (1989) The retinoblastoma protein is phosphorylated during specific phases of the cell cycle. Cell 58:1097–1105

Cairns P, Proctor AJ, Knowles MA (1991) Loss of heterozygosity at the RB locus is frequent and correlates with muscle invasion in bladder carcinoma. Oncogene 6:2305–2309

Coombs LM, Pigott DA, Eydmann ME, Proctor AJ, Knowles MA (1993) Reduced expression of TGFß is associated with advanced disease in transitional cell carcinoma. Br J Cancer 67:578–584

Cordon-Cardo C, Wartinger D, Petrylak D, Dalbagni G, Fair WR, Fuks Z, Reuter VE (1992) Altered expression of retinoblastoma gene product: prognostic indicator in bladder cancer. J Natl Cancer Inst 84:1251–1256

Cowell J, Hungeford J, Rutland P, et al (1987) A chromosomal breakpoint that separates the esterase D and retinoblastoma predisposition loci in patients with del(13)(q14q31). Cancer Genet Cytogenet 27:27–31

Friend SH, Bernards R, Rogel J (1986) A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma. Nature 323:643–646

Geradts J, Hu S-X, Lincoln CE, Benedict WF, Xu H-J (1994) Aberrant Rb gene expression in routinely processed, archival tumor tissues determined by three different anti-Rb antibodies. Int J Cancer 58: 161–167

Goodrich DW, Chen Y, Scully P, Lee WH (1992) Expression of the retinoblastoma gene product in bladder carcinoma cells associates with a low frequency of tumour formation. Cancer Res 52: 1968–1973

Harbour JW, Lai SL, Whang PJ, et al (1988) Abnormalities in structure and expression of the human retinoblastoma gene in SCLC. Science 241:353–357

Ishikawa J, Xu HJ, Hu SX, Yandell DW, Maeda S, Kamidono S, Benedict WF, Takahashi R (1991) Inactivation of the retinoblastoma gene in human bladder and renal cell carcinomas. Cancer Res 51:5736–5743

Isobe M, Emanuel BS, Givol D, Oren M, Croce CM (1986) Localization of gene for human p53 tumor antigen to band 17p13. Nature 320:84–85

Lane DP, Benchimol S (1990) p53: oncogene or anti-oncogene. Genes Dev 4:1–8

Lee EY, To H, Shew JY, et al (1988) Inactivation of the retinoblastoma susceptibility gene in human breast cancers. Science 241:218–221

Lee E, Desu M (1972) A computer program for comparing k samples with right censored data. Comput Program Biomed 2:315–318

Lee WH, Bookstein R, Hong F, Young LJ, Shew JY, Lee EY-HP (1987a) Human retinoblastoma suspectibility gene: cloning, identification and sequence. Science 235:1394–1399

Lee W-H, Shew J-Y, Hong F, Sery T, Donoso LA, Young LJ, Bookstein R, Lee EY-HP (1987b) The retinoblastoma suspectibility gene product is a nuclear phosphoprotein associated with DNA binding activity. Nature 329:642–645

Lipponen PK (1993a) Over-expression of p53 nuclear oncoprotein in transitional-cell bladder cancer and its prognostic value. Int J Cancer 53:365–370

Lipponen P (1993b) Expression of c-erbB-2 oncoprotein in transitional cell bladder cancer. Eur J Cancer 29 A:749–753

Lipponen P, Eskelinen M (1994) Expression of epidermal growth factor receptor in bladder cancer as related to established prognostic factors, oncoprotein (c-erbB-2, p53) expression and longterm prognosis. Br J Cancer 69:1120–1125

Lipponen PK, Eskelinen MJ, Jauhiainen K, Harju E, Terho R, Haapasalo H (1992) Independent clinical, histological and quantitative prognostic factors in transitional-cell bladder tumours, with special reference to mitotic frequency. Int J Cancer 51:396–403

Lipponen PK, Nordling S, Eskelinen MJ, Jauhiainen K, Terho R, Harju E (1993) Flow cytometry in comparison with mitotic index in predicting disease outcome in transitional-cell bladder cancer. Int J Cancer 53:42–47

Logothesis CL, Xu HJ, Ro JY, Hu SX, Sahin A, Ordonez N, Benedict WF (1992) Altered expression of retinoblastoma protein and known prognostic variables in locally advanced bladder cancer. J Natl Cancer Inst 84:1256–1261

Mercer WE, Shields MT, Lin D, Appella E, Ullrich SJ (1991) Growth suppression induced by wild-type p53 protein is accompanied by selective down-regulation of proliferating cell nuclear antigen expression. Proc Natl Acad Sci USA 88:1958–1962

Mostofi FK (1973) International histological classification of tumours. 10. Histological typing of urinary bladder tumours. WHO, Geneva

Sarkis AS, Dalbagni G, Cordon-Cardo C, Zhang Z-F, Sheinfeld J, Fair WR, Herr HW, Reuter VE (1993) Nuclear overexpression of p53 protein in transitional bladder carcinoma: a marker for disease progression. J Natl Cancer Inst 85:53–59

Sidransky D, Von Eschenbach A, Tsai YC, Jones P, Summerhayes I, Marshall F, Paul M, Green P, Hamilton SR, Frost P, Vogelstein B (1991) Identification of p53 gene mutations in bladder cancers and urine samples. Science 252:706–709

Silvestrini R, Benini E, Daidone MG, Veneroni S, Boracchi P, Cappelletti V, Di Fronzo G, Veromesi U (1993) p53 as an independent prognostic marker in lymph node-negative breast cancer patients. J Natl Cancer Inst 85:965–970

Strohmayer T, Reissmann P, Cordon-Carbo C, Hartmann M, Ackermann R, Slamon D (1991) Correlation between retinoblastoma gene expression and differentiation in human testicular tumours. Proc Natl Acad Sci USA 88:6662–6666

Takahashi R, Hashimoto T, Xu HJ, Hu SX, Matsui T, Miki T, BigoMarshall H, Aaronson SA, Benedict WF (1991) The retinoblastoma gene functions as a growth and tumor suppressor in human bladder carcinoma cells. Proc Natl Acad Sci USA 88:5257–5261

UICC (International Union Against Cancer) (1978) TNM classification of malignant tumours. UICC, Geneva

Visakorpi T, Kallioniemi O-P, Heikkinen A, Koivula T, Isola J (1992) Small subgroup of aggressive, highly proliferative prostatic carcinomas defined by p53 accumulation. J Natl Cancer Inst 84: 883–887

Wiman KG (1993) The retinoblastoma gene: role in cell cycle control and cell differentiation. FASEB J 7:841–845

Xu HJ, Cairns P, Hu AX, Knowles MA, Benedict W (1993) Loss of Rb protein expression in primary bladder cancer correlates with loss of heterozygosity at the Rb locus and tumor progression. Int J Cancer 53:781–784

Zingg EJ, Wallace DNA (1985) Bladder cancer. Springer, Berlin Heidelberg New York, pl 1–21, 161–191

Thông tin
Thông tin xuất bản

Journal of Cancer Research and Clinical Oncology

Tập 121

44-50

Thông tin tác giả