The p53 Tumor Suppressor Gene and Nuclear Protein: Basic Science Review and Relevance in the Management of Bladder Cancer
Abstract
Purpose:
An extensive body of literature regarding p53 has accumulated during the last 2 decades. The cellular mechanisms of p53 are complex yet well-defined, whereas its clinical usefulness in the management of bladder cancer remains controversial. We outline the basic constitutive functions of p53 and summarize its current role in the management of transitional cell carcinoma of the bladder.
Materials and Methods:
We conducted a MEDLINE based literature review concerning the fundamental mechanisms of p53 and its role in the management of bladder cancer.
Results:
The p53 gene is a tumor suppressor gene that acts as “guardian of the genome.” Many diverse cellular events, including DNA damage and hypoxia, activate the p53 gene. The p53 protein functions as a transcription factor, regulating downstream genes involved in cell cycle arrest, DNA repair and programmed cell death. Loss of p53 function confers genomic instability, impaired apoptosis and diminished cell cycle restraint. Therefore, p53 mutations select for certain critical features of malignancy.
Alteration of p53 is the most common mutation in human cancer.:
Roughly half of all human malignancies, including many urological cancers, exhibit p53 mutations. In bladder cancer p53 mutations have been associated with higher tumor grade and advanced stage, as well as progression of superficial disease to muscle invasion. Moreover, p53 nuclear over expression appears to be an independent predictor of disease progression and decreased survival after cystectomy.
Conclusions:
The importance of p53 mutation in tumor cell biology is irrefutable. Wild-type p53 mediates imperative functions such as regulation of the cell cycle and programmed cell death. Deficiency of p53 function by mutation or inactivation abrogates normal cell cycle checkpoints and apoptosis, generating a favorable milieu for genomic instability and carcinogenesis. However, despite the manifest importance of p53 in human malignancy, its current role in the management of bladder cancer appears somewhat limited. A multitude of retrospective studies have associated p53 mutations with adverse outcomes in superficial and muscle invasive disease. Nonetheless, randomized prospective studies are needed to determine the potential clinical implications of p53 in bladder cancer.
References
- 1 : Characterization of a 54K dalton cellular SV40 tumor antigen present in SV40 transformed cells and uninfected embryonal carcinoma cells. Cell1979; 17: 43. Google Scholar
- 2 : The p53 proto-oncogene can act as a suppressor of transformation. Cell1989; 57: 1083. Google Scholar
- 3 : Suppression of human colorectal carcinoma cell growth by wild-type p53. Science1990; 249: 912. Google Scholar
- 4 : p53: puzzle and paradigm. Genes Dev1996; 10: 1054. Google Scholar
- 5 : p53, the cellular gatekeeper for growth and division. Cell1997; 88: 323. Google Scholar
- 6 : Database of p53 gene somatic mutations in human tumors and cell lines. Nucleic Acids Res1994; 22: 3551. Google Scholar
- 7 : p53: an important key to understanding urologic cancer. AUA Update Series1995; XIV: 258. Google Scholar
- 8 : V(D)J recombination activates a p53-dependent DNA damage checkpoint in scid lymphocyte precursors. Genes Dev1996; 10: 2038. Google Scholar
- 9 : A reversible, p53-dependent G0/G1 cell cycle arrest induced by ribonucleotide depletion in the absence of detectable DNA damage. Genes Dev1996; 10: 934. Google Scholar
- 10 : p53 in growth control and neoplasia. Biochim Biophys Acta1996; 1287: 77. Google Scholar
- 11 : p53 is required for radiation-induced apoptosis in mouse thymocytes. Nature1993; 362: 847. Google Scholar
- 12 : Myc-mediated apoptosis requires wild-type p53 in a manner independent of cell cycle arrest and the ability of p53 to induce p21waf1/cip1. Genes Dev1994; 8: 2817. Google Scholar
- 13 : Wild-type p53 induces apoptosis of myeloid leukaemic cells that is inhibited by interleukin-6. Nature1991; 352: 345. Google Scholar
- 14 : Growth suppression of Friend virus-transformed erythroleukemia cells by p53 protein is accompanied by hemoglobin production and is sensitive to erythropoietin. Mol Cell Biol1993; 13: 1456. Google Scholar
- 15 : The WT1 gene product stabilizes p53 and inhibits p53-mediated apoptosis. Genes Dev1995; 9: 2143. Google Scholar
- 16 : Abnormal centrosome amplification in the absence of p53. Science1996; 271: 1744. Google Scholar
- 17 : A p53-dependent mouse spindle checkpoint. Science1995; 267: 1353. Google Scholar
- 18 : p53 mutant mice that display early ageing-associated phenotypes. Nature2002; 415: 45. Google Scholar
- 19 : P53 and angiogenesis. Biochim Biophys Acta1996; 1287: 63. Google Scholar
- 20 : The modulation of thrombospondin and other naturally occurring inhibitors of angiogenesis during tumor progression. Breast Cancer Res Treat1995; 36: 119. Google Scholar
- 21 : Control of angiogenesis in fibroblasts by p53 regulation of thrombospondin-1. Science1994; 265: 1582. Google Scholar
- 22 : p53 and microvessel density in primary resection specimens of superficial bladder cancer. J Urol2002; 167: 1469. Abstract, Google Scholar
- 23 : Human papillomavirus and bladder cancer. Biomed Pharmacother1997; 51: 252. Google Scholar
- 24 : Prevalence of human papillomaviruses 16 and 18 in transitional cell carcinoma of bladder. Chin Med J1993; 106: 494. Google Scholar
- 25 : The p53-mdm-2 autoregulatory feedback loop. Genes Dev1993; 7: 1126. Google Scholar
- 26 : Oncogene amplification in urothelial cancers with p53 gene mutation or MDM2 amplification. J Natl Cancer Inst1994; 86: 1331. Google Scholar
- 27 : Identification of a novel p53 functional domain that is necessary for efficient growth suppression. Proc Natl Acad Sci U S A1996; 93: 15335. Google Scholar
- 28 : p53 mutations in human bladder cancer: genotypic versus phenotypic patterns. Int J Cancer1994; 56: 347. Google Scholar
- 29 : p53 nuclear protein accumulation correlates with mutations in the p53 gene, tumor grade, and stage in bladder cancer. Am J Pathol1993; 143: 1389. Google Scholar
- 30 : Predictive value of p53 mutations analyzed in bladder washings for progression of high-risk superficial bladder cancer. Clin Cancer Res1996; 2: 1055. Google Scholar
- 31 : Does p53 immunostaining improve diagnostic accuracy in urine cytology?. Diagn Cytopathol1997; 17: 436. Google Scholar
- 32 : Correlation and prognostic significance of p53, p21WAF1/CIP1 and Ki-67 expression in patients with superficial bladder tumors treated with bacillus Calmette-Guerin intravesical therapy. J Urol1999; 161: 792. Link, Google Scholar
- 33 : p53 expression compared with other prognostic factors in OMS grade-I stage-Ta transitional cell carcinoma of the bladder. Eur Urol1997; 32: 229. Google Scholar
- 34 : Stage progression in Ta papillary urothelial tumors: relationship to grade, immunohistochemical expression of tumor markers, mitotic frequency and DNA ploidy. J Urol2001; 165: 1124. Link, Google Scholar
- 35 : Nuclear overexpression of p53 protein in transitional cell bladder carcinoma: a marker for disease progression. J Natl Cancer Inst1993; 85: 53. Google Scholar
- 36 : The influence of the level of lamina propria invasion and the prevalence of p53 nuclear accumulation on survival in stage T1 transitional cell bladder cancer. J Urol1998; 159: 91. Link, Google Scholar
- 37 : The prognostic value of p53 in superficially infiltrating transitional cell carcinoma. Scand J Urol Nephrol1995; 29: 491. Google Scholar
- 38 : The predictive value of muscularis mucosae invasion and p53 over expression on progression of stage T1 bladder carcinoma. J Urol2001; 165: 42. Link, Google Scholar
- 39 : Nuclear accumulation of mutant p53 protein: a possible predictor of failure of intravesical therapy in bladder cancer. Br J Urol1997; 79: 373. Google Scholar
- 40 : Significance of p53 overexpression in urinary bladder transitional cell carcinoma in situ before and after bacillus Calmette-Guerin treatment. Urology1997; 49: 541. Google Scholar
- 41 : Overexpression of p53 protein in a high-risk population of patients with superficial bladder cancer before and after bacillus Calmette-Guerin therapy: correlation to clinical outcome. J Clin Oncol1996; 14: 2646. Google Scholar
- 42 : p53 status does not predict initial clinical response to bacillus Calmette-Guerin intravesical therapy in T1 bladder tumors. J Urol1998; 159: 1079. Link, Google Scholar
- 43 : p53 and erbB-2 protein overexpression are associated with early invasion and metastasis in bladder cancer. Virchows Arch A Pathol Anat Histopathol1993; 423: 329. Google Scholar
- 44 : Over-expression of p53 nuclear oncoprotein in transitional-cell bladder cancer and its prognostic value. Int J Cancer1993; 53: 365. Google Scholar
- 45 : TP53 accumulation predicts improved survival in patients resistant to systemic cisplatin-based chemotherapy for muscle-invasive bladder cancer. Clin Cancer Res1999; 5: 3500. Google Scholar
- 46 : Can p53 help select patients with invasive bladder cancer for bladder preservation?. J Urol1999; 161: 20. Link, Google Scholar
- 47 : Prognostic value of p53 nuclear overexpression in patients with invasive bladder cancer treated with neoadjuvant MVAC. J Clin Oncol1995; 13: 1384. Google Scholar
- 48 : Prognostic value of p53 in muscle-invasive bladder cancer treated with preoperative radiotherapy. Urology1996; 47: 305. Google Scholar
- 49 : p53 and Rb immunostaining in locally advanced bladder cancer: relation to prognostic variables and predictive value for the local response to radical radiotherapy. Eur Urol1995; 28: 135. Google Scholar
- 50 : p53, p21 and mdm2 expression vs the response to radiotherapy in transitional cell carcinoma of the bladder. BJU Int2001; 88: 202. Google Scholar
- 51 : Clinical significance of DNA ploidy and S-phase fraction and their relation to p53 protein, c-erbB-2 protein and HCG in operable muscleinvasive bladder cancer. Br J Cancer1993; 68: 572. Google Scholar
- 52 : Accumulation of nuclear p53 and tumor progression in bladder cancer. N Engl J Med1994; 331: 1259. Google Scholar
- 53 : p53 overexpression as a prognostic factor for advanced stage bladder cancer. Eur J Cancer1995; 31A: 2243. Google Scholar
- 54 : Structural alteration of p53 protein in patients with muscle invasive bladder transitional cell carcinoma. J Urol2001; 166: 2155. Abstract, Google Scholar
- 55 : p53 nuclear accumulation is not associated with decreased disease-free survival in patients with node positive transitional cell carcinoma of the bladder. J Urol2000; 164: 1177. Link, Google Scholar
- 56 : Multifocal transitional cell cancer and p53 mutation analysis. J Urol1998; 160: 124. Link, Google Scholar
- 57 : The relationship among multiple recurrences, progression and prognosis of patients with stages TA and T1 transitional cell cancer of the bladder followed for at least 20 years. J Urol1995; 153: 1823. Link, Google Scholar
- 58 : Predicting cancer progression in patients with stage T1 bladder carcinoma. J Clin Oncol1999; 17: 3182. Google Scholar
- 59 : Association of P53 nuclear overexpression and tumor progression in carcinoma in situ of the bladder. J Urol1994; 152: 388. Link, Google Scholar
- 60 : Intravesical bacillus Calmette-Guerin (BCG) as inducer of tumor-suppressing proteins p53 and p21 Waf1-Cip1 during treatment of superficial bladder cancer. J Urol1999; 162: 225. Link, Google Scholar
- 61 : P53 immunohistochemistry as a prognostic marker in bladder cancer: the ISBC combined analysis. J Urol1999; 161: 153. abstract 585. Google Scholar
- 62 : Immunohistochemical analysis of p53 and proliferating cell nuclear antigen (PCNA) in bladder cancer: positive immunostaining and radiosensitivity. Int J Urol1995; 2: 302. Google Scholar
- 63 : Relationship between radiation response and p53 status in human bladder cancer cells. Int J Radiat Biol1997; 72: 11. Google Scholar
- 64 : Prognostic factors in transitional cell cancer of the bladder: an emerging role for Bcl-2 and p53. Radiother Oncol2001; 61: 169. Google Scholar
- 65 : Abrogation of apoptosis induced by DNA-damaging agents in human bladder-cancer cell lines with p21/WAF1/CIP1 and/or p53 gene alterations. Int J Cancer1996; 68: 501. Google Scholar
- 66 : Molecular determinants of outcome in bladder cancer. Cancer J Sci Am1999; 5: 2. Google Scholar
- 67 : Uncoupling of S phase and mitosis induced by anticancer agents in cells lacking p21. Nature1996; 381: 713. Google Scholar
- 68 : Functional p53 mutation as a molecular determinant of paclitaxel and gemcitabine susceptibility in human bladder cancer. J Urol2001; 166: 482. Link, Google Scholar
- 69 : In vivo antitumor activity of ONYX-015 is influenced by p53 status and is augmented by radiotherapy. Cancer Res2000; 60: 1193. Google Scholar
- 70 : ONYX-015, an E1B gene-attenuated adenovirus, causes tumor-specific cytolysis and antitumoral efficacy that can be augmented by standard chemotherapeutic agents. Nat Med1997; 3: 639. Google Scholar
- 71 : A phase I study of Onyx-015, an E1B attenuated adenovirus, administered intratumorally to patients with recurrent head and neck cancer. Clin Cancer Res2000; 6: 798. Google Scholar
- 72 : A controlled trial of intratumoral ONYX-015, a selectively-replicating adenovirus, in combination with cisplatin and 5-fluorouracil in patients with recurrent head and neck cancer. Nat Med2000; 6: 879. Google Scholar
- 73 : Gene therapy for bladder cancer using adenoviral vector. Mol Urol2001; 5: 47. Google Scholar
- 74 : p53 Mutation in bladder cancer patients in Japan and inhibition of growth by in vitro adenovirus-mediated wild-type p53 transduction in bladder cancer cells. Mol Urol2001; 5: 53. Google Scholar
- 75 : p53 autoantibodies in patients with urological tumours. Br J Urol1998; 82: 721. Google Scholar
From the Department of Urology, Northwestern University Medical School, Chicago, Illinois
© 2003 by American Urological Association, Inc.
