Biomarkers

Biomarkers are used to determine the aggressiveness of cancer. A wealth of clinically useful information is available in even the smallest tissue specimens of the prostate, including biopsies and transurethral resections. Substantial effort has been expanded in the past decade in describing the available factors and determining their predictive value for staging, cancer recurrence and survival.

Proliferating Cell Nuclear Antigen (PCNA)
High PCNA labeling indices may indicate progression of prostate cancer,1,2 and may be an independent prognostic indicator.1

Ki-67 and MIB-1
Recognizes a nuclear antigen present in proliferating cells but absent in resting cells. Ki-67 labeling index may discriminate between organ confined and metastatic cancer.

Microvessel Density (MVD)
Helpful in predicting pathologic stage and patient outcome in prostate cancer.

Bcl-2

  • Highlights the Bcl-2 protein which functions as a blocker of apoptosis and programmed cell death.
  • Expression of Bcl-2 is normally restricted to the basal cell layer of the normal and hyperplastic prostatic epithelium.
  • Overexpression of Bcl-2 is present in high-grade prostatic intraepithelial neoplasia.3,4

p53

  • Identifies p53 (a regulator of the cell cycle) immunoreactivity in cancer cells.
  • Most immunohistochemical studies concluded that mutant p53 expression is a late event in localized prostate cancer,6-8 usually present in higher (>7) grade cancer.5,9,10

pP27

  • The cyclin-dependent kinase inhibitor (p27Kip1) negatively regulates cell proliferation.
  • Decreased p27Kip1 expression may be an independent predictor for cancer recurrence and long-term survival of prostate cancer.11-14

1. Grignon, D. J. and Hammond, E. H.: College of American Pathologists Conference XXVI on clinical relevance of prognostic markers in solid tumors. Report of the Prostate Cancer Working Group. Archives of Pathology and Laboratory Medicine, 119: 1122-1126, 1995.

2. Idikio, H. A.: Expression of proliferating cell nuclear antigen in node-negative human prostate cancer. Anticancer Res., 16: 2607-2611, 1996.

3. Hockenbery, D., Zutter, M., Hickey, W., Nahm, M., and Korsmeyer, S. J.: bcl-2 protein is topographically restricted to tissues characterized by apoptotic cell death. Proceedings of the National Academy of Science USA, 88: 6961-6965, 1991.

4. Tu, H., Jacobs, S. C., Borkowski, A., and Kyprianou, N.: Incidence of apoptosis and cell proliferation in prostate cancer: relationship with TGF-beta1 and bcl-2 expression. Int. J. Cancer, 69: 357-363, 1996.

5. Navone, N. M., Troncoso, P., Pisters, L. L., Goodrow, T. L., Palmer, J. L., Nichols, W. W., von Eschenbach, A. C., and Conti, C. J.: p53 protein accumulation and gene mutation in the progression of human prostate carcinoma. J. Nat. Cancer Inst., 85: 1657-1669, 1993.

6. Ittman, M., Wieczorek, R., Heller, P., Dave, A., Provet, J., and Krolewski, J.: Alterations in the p53 and MDC-2 genes are infrequent in clinically localized stage B prostate adenocarcinomas. Am. J. Pathol., 145: 287-293, 1994.

7. Hall, M. C., Navone, N. M., Troncoso, P., Pollack, A., Zagars, G. K., von Eschenbach, A. C., Conti, C. J., and Chung, L. W.: Frequency and characterization of p53 mutations in clinically localized prostate cancer. Urology, 45: 470-475, 1995.

8. Mottaz, A. E., Markwalder, R., Fey, M. F., Klima, I., Merz, V. W., Thalmann, G. N., Ball, R. K., and Studer, U. E.: Abnormal p53 expression is rare in clinically localized human prostate cancer: comparison between immunohistochemical and molecular detection of p53 mutations. The Prostate, 31: 209-215, 1997.

9. Kallakury, B. V., Figge, J., Ross, J. S., Fisher, H. A., Figge, H. L., and Jennings, T. A.: Association of p53 immunoreactivity with high Gleason tumor grade in prostate adenocarcinoma. Hum. Pathol., 25: 92-97, 1994.

10. Stackhouse GB, Sesterhenn IA, Bauer JJ, Mostofi FK, Connelly RR, Srivastava SK, Moul JW. p53 and bcl-2 immunohistochemistry in pretreatment prostate needle biopsies to predict recurrence of prostate cancer after radical prostatectomy. J Urol.162:2040-5, 1999.

11. Tsihlias, J., Kapusta, L. R., DeBoer, G., Morava-Protzner, I., Zbieranowski, I., Bhattacharya, N., Catzavelos, G. C., Klotz, L. H., and Slingerland, J. M.: Loss of cyclin-dependent kinase inhibitor p27Kip1 is a novel prognostic factor in localized human prostate adenocarcinoma. Cancer Res., 58: 542-548, 1998.

12. Kuczyk M, Machtens S, Hradil K, Schubach J, Christian W, Knuchel R, Hartmann J, Bokemeyer C, Jonas U, Serth J. Predictive value of decreased p27Kip1 protein expression for the recurrence-free and long-term survival of prostate cancer patients. Br J Cancer 81:1052-8, 1999.

13. Drobnjak M, Melamed J, Taneja S, Melzer K, Wieczorek R, Levinson B, Zeleniuch-Jacquotte A, Polsky D, Ferrara J, Perez-Soler R, Cordon-Cardo C, Pagano M, Osman I. Altered expression of p27 and Skp2 proteins in prostate cancer of African-American patients. Clin Cancer Res. 2003 Jul;9(7):2613-9.

14. Halvorsen OJ, Haukaas SA, Akslen LA. Combined loss of PTEN and p27 expression is associated with tumor cell proliferation by Ki-67 and increased risk of recurrent disease in localized prostate cancer. Clin Cancer Res. 2003 Apr;9(4):1474-9.