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Are biomarkers evaluated in biopsy specimens predictive of prostate cancer aggressiveness?

  • Original Article – Cancer Research
  • Published:
Journal of Cancer Research and Clinical Oncology Aims and scope Submit manuscript

Abstract

Purpose

To evaluate biomarkers involved in biological pathways for prostate cancer (PCa) progression, measured in biopsy specimens, in order to distinguish patients at higher risk for fatal PCa and thus improve the initial management of disease.

Methods

Retrospective case–control study. In 129 PCa patients who underwent ultrasound-guided needle prostate biopsy and subsequent radical prostatectomy from 1987 to 1999 at the University Hospital of Careggi, we evaluated: (1) mRNA expression of the serine 2 (TMPRSS2): erythroblastosis virus E26 oncogene homolog (ERG); (2) expression of matrix metalloproteinases (MMP)-2 and 9 (epithelial and stromal); (3) expression of androgen receptor; (4) expression of prognostic marker Ki67 (MIB1); (5) presence and typing of human papilloma virus; (6) DNA methylation of CpG islands of several genes involved in PCa progression.

Results

The cohort consists of 38 cases (patients with PCa and died of PCa within 10 years from diagnosis) and 91 controls (patients with PCa but alive 10 years after diagnosis). Gleason bioptic score, epithelial MMP expression and SERPINB5 methylation correlated with statistically significant increase in death risk OR. Compared with patients with high level of MMP, patients with low level of MMP had OR for specific death 4.78 times higher (p = 0.0066). After adjustment for age and Gleason score, none of the investigated biomarkers showed increased OR for PCa death.

Conclusions

Our preliminary results suggest that evaluation, in prostate biopsy specimens, of a panel of biomarkers known to be involved in PCa progression is poorly indicative of tumor outcome.

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References

  • Albertsen PC, Hanley JA, Fine J (2005) 20-Year outcomes following conservative management of clinically localized prostate cancer. JAMA 293:2095–2101

    Article  PubMed  CAS  Google Scholar 

  • Bastian PJ, Palapattu GS, Yegnasubramanian S, Lin X, Rogers CG, Mangold LA, Trock B, Eisenberger M, Partin AW, Nelson WG (2007) Prognostic value of preoperative serum cell-free circulating DNA in men with prostate cancer undergoing radical prostatectomy. Clin Cancer Res 13:5361–5367

    Article  PubMed  CAS  Google Scholar 

  • Berardi R, Morgese F, Onofri A, Mazzanti P, Pistelli M, Ballatore Z, Savini A, De Lisa M, Caramenti Rinaldi S, Pagliaretta S, Santoni M, Pierantoni C, Cascinu S (2013) Role of Maspin in cancer. Clin Transl Med 2:8

    Article  PubMed  PubMed Central  Google Scholar 

  • Bonaccorsi L, Nesi G, Nuti F, Paglierani M, Krausz C, Masieri L, Serni S, Proietti-Pannunzi L, Fang Y, Jhanwar SC, Orlando C, Carini M, Forti G, Baldi E, Luzzatto L (2009) Persistence of expression of the TMPRSS2:ERG fusion gene after pre-surgery androgen ablation may be associated with early prostate specific antigen relapse of prostate cancer: preliminary results. J Endocrinol Invest 32:590–596

    Article  PubMed  CAS  Google Scholar 

  • Boxler S, Djonov V, Kessler TM, Hlushchuk R, Bachmann LM, Held U, Markwalder R, Thalmann GN (2010) Matrix metalloproteinases and angiogenic factors: predictors of survival after radical prostatectomy for clinically organ-confined prostate cancer? Am J Pathol 177:2216–2224

    Article  PubMed  PubMed Central  Google Scholar 

  • Coffey DS (1993) Prostate cancer. An overview of an increasing dilemma. Cancer 71:880–886

    Article  PubMed  CAS  Google Scholar 

  • Corona G, Baldi E, Maggi M (2011) Androgen regulation of prostate cancer: where are we now? J Endocrinol Invest 34:232–243

    Article  PubMed  CAS  Google Scholar 

  • Cuzick J, Thorat MA, Andriole G, Brawley OW, Brown PH, Culig Z, Eeles RA, Ford LG, Hamdy FC, Holmberg L, Ilic D, Key TJ, La Vecchia C, Lilja H, Marberger M, Meyskens FL, Minasian LM, Parker C, Parnes HL, Perner S, Rittenhouse H, Schalken J, Schmid HP, Schmitz-Dräger BJ, Schröder FH, Stenzl A, Tombal B, Wilt TJ, Wolk A (2014) Prevention and early detection of prostate cancer. Lancet Oncol 15:e484–e492 (Review)

    Article  PubMed  PubMed Central  Google Scholar 

  • de Koning HJ, Auvinen A, Berenguer Sanchez A, Calais da Silva F, Ciatto S, Denis L, Gohagan JK, Hakama M, Hugosson J, Kranse R, Nelen V, Prorok PC, Schröder FH (2002) European Randomized Screening for Prostate Cancer (ERSPC) Trial; International Prostate Cancer Screening Trials Evaluation Group. Large-scale randomized prostate cancer screening trials: program performances in the European Randomized Screening for Prostate Cancer trial and the Prostate, Lung, Colorectal and Ovary cancer trial. Int J Cancer 97:237–244

    Article  PubMed  CAS  Google Scholar 

  • Diaw L, Woodson K, Gillespie JW (2007) Prostate cancer epigenetics: a review on gene regulation. Gene Regul Syst Biol 1:313–325

    Google Scholar 

  • Domann FE, Rice JC, Hendrix MJ, Futscher BW (2000) Epigenetic silencing of Maspin gene expression in human breast cancers. Int J Cancer 85:805–810

    Article  PubMed  CAS  Google Scholar 

  • Draisma G, Boer R, Otto SJ, van der Cruijsen IW, Damhuis RA, Schröder FH, de Koning HJ (2003) Lead times and overdetection due to prostate-specific antigen screening: estimates from the European Randomized Study of Screening for Prostate Cancer. J Natl Cancer Inst 95:868–878

    Article  PubMed  Google Scholar 

  • Eggener SE, Scardino PT, Walsh PC, Han M, Partin AW, Trock BJ, Feng Z, Wood DP, Eastham JA, Yossepowitch O, Rabah DM, Kattan MW, Yu C, Klein EA, Stephenson AJ (2011) Predicting 15-year prostate cancer specific mortality after radical prostatectomy. J Urol 185:869–875

    Article  PubMed  PubMed Central  Google Scholar 

  • Escaff S, Fernández JM, González LO, Suárez A, González-Reyes S, González JM, Vizoso FJ (2010) Study of matrix metalloproteinases and their inhibitors in prostate cancer. Br J Cancer 102:922–929

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Escaff S, Fernández JM, González LO, Suárez A, González-Reyes S, González JM, Vizoso FJ (2011) Collagenase-3 expression by tumor cells and gelatinase B expression by stromal fibroblast-like cells are associated with biochemical recurrence after radical prostatectomy in patients with prostate cancer. World J Urol 29:657–663

    Article  PubMed  CAS  Google Scholar 

  • Gacci M, Baldi E, Tamburrino L, Detti B, Livi L, De Nunzio C, Tubaro A, Gravas S, Serni S, Carini M (2014) Quality of life and sexual health in the aging of PCa survivors. Int J Endocrinol 2014:470592 (Review)

    Article  PubMed  PubMed Central  Google Scholar 

  • Ganz PA, Barry JM, Burke W, Col NF, Corso PS, Dodson E, Hammond ME, Kogan BA, Lynch CF, Newcomer L, Seifter EJ, Tooze JA, Viswanath KV, Wessells H (2011) NIH State-of-the-Science Conference Statement: role of active surveillance in the management of men with localized prostate cancer. NIH Consens State Sci Statements 28:1–27

    PubMed  Google Scholar 

  • Ganz PA, Barry JM, Burke W, Col NF, Corso PS, Dodson E, Hammond ME, Kogan BA, Lynch CF, Newcomer L, Seifter EJ, Tooze JA, Viswanath K, Wessells H (2012) National Institute of Health State-of-the-Science Conference: role of active surveillance in the management of men with localized prostate cancer. Ann Intern Med 156(8):591–595

    Article  PubMed  Google Scholar 

  • Greenlee RT, Hill-Harmon MB, Murray T, Thun M (2001) Cancer statistics. CA Cancer J Clin 51(1):15–36

    Article  PubMed  CAS  Google Scholar 

  • Hadler-Olsen E, Winberg JO, Uhlin-Hansen L (2013) Matrix metalloproteinases in cancer: their value as diagnostic and prognostic markers and therapeutic targets. Tumour Biol 34:2041–2051

    Article  PubMed  CAS  Google Scholar 

  • Heijnsdijk EA, Wever EM, Auvinen A, Hugosson J, Ciatto S, Nelen V, Kwiatkowski M, Villers A, Páez A, Moss SM, Zappa M, Tammela TL, Mäkinen T, Carlsson S, Korfage IJ, Essink-Bot ML, Otto SJ, Draisma G, Bangma CH, Roobol MJ, Schröder FH, de Koning HJ (2012) Quality-of-life effects of prostate-specific antigen screening. N Engl J Med 367:595–605

    Article  PubMed  CAS  Google Scholar 

  • Hurtubise A, Momparler RL (2004) Evaluation of antineoplastic action of 5-aza-2′-deoxycytidine (Dacogen) and docetaxel (Taxotere) on human breast, lung and prostate carcinoma cell lines. Anticancer Drugs 15:161–167

    Article  PubMed  CAS  Google Scholar 

  • Li X, Yin S, Meng Y, Sakr W, Sheng S (2006) Endogenous inhibition of histone deacetylase 1 by tumor-suppressive Maspin. Cancer Res 66:9323–9329

    Article  PubMed  CAS  Google Scholar 

  • Lin PC, Giannopoulou EG, Park K, Mosquera JM, Sboner A, Tewari AK, Garraway LA, Beltran H, Rubin MA, Elemento O (2013) Epigenomic alterations in localized and advanced prostate cancer. Neoplasia 15:373–383

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Minner S, Enodien M, Sirma H, Luebke AM, Krohn A, Mayer PS, Simon R, Tennstedt P, Müller J, Scholz L, Brase JC, Liu AY, Schlüter H, Pantel K, Schumacher U, Bokemeyer C, Steuber T, Graefen M, Sauter G, Schlomm T (2011) ERG status is unrelated to PSA recurrence in radically operated prostate cancer in the absence of antihormonal therapy. Clin Cancer Res 17:5878–5888

    Article  PubMed  CAS  Google Scholar 

  • Ozden F, Saygin C, Uzunaslan D, Onal B, Durak H, Aki H (2013) Expression of MMP-1, MMP-9 and TIMP-2 in prostate carcinoma and their influence on prognosis and survival. J Cancer Res Clin Oncol 139:1373–1382

    Article  PubMed  CAS  Google Scholar 

  • Paci E, Crocetti E, Miccinesi G, Benvenuti A, Intrieri T, Sacchettini C, Giovannetti L (2007). Tuscany cancer registry. In: Curado MP, Edwards B, Shin HR, Storm H, Ferlay J, Heanue M, Boyle P (eds) Cancer incidence in five continents, Vol. IX IARC Scientific Publications No. 160. IARC, Lyon

  • Pascale M, Pracella D, Barbazza R, Marongiu B, Roggero E, Bonin S, Stanta G (2013) Is human papillomavirus associated with prostate cancer survival? Dis Markers 35:607–613

    Article  PubMed  PubMed Central  Google Scholar 

  • Pellikainen JM, Ropponen KM, Kataja VV, Kellokoski JK, Eskelinen MJ, Kosma VM (2004) Expression of matrix metalloproteinase (MMP)-2 and MMP-9 in breast cancer with a special reference to activator protein-2, HER2, and prognosis. Clin Cancer Res 10:7621–7628

    Article  PubMed  CAS  Google Scholar 

  • Pettersson A, Graff RE, Bauer SR, Pitt MJ, Lis RT, Stack EC, Martin NE, Kunz L, Penney KL, Ligon AH, Suppan C, Flavin R, Sesso HD, Rider JR, Sweeney C, Stampfer MJ, Fiorentino M, Kantoff PW, Sanda MG, Giovannucci EL, Ding EL, Loda M, Mucci LA (2012) The TMPRSS2:ERG rearrangement, ERG expression, and prostate cancer outcomes: a cohort study and meta-analysis. Cancer Epidemiol Biomark Prev 21:1497–1509

    Article  Google Scholar 

  • Romero Otero J, Garcia Gomez B, Campos Juanatey F, Touijer KA (2014) Prostate cancer biomarkers: an update. Urol Oncol 32:252–260

    Article  PubMed  CAS  Google Scholar 

  • Roobol MJ, Zappa M, Määttänen L, Ciatto S (2007) The value of different screening tests in predicting prostate biopsy outcome in screening for prostate cancer data from a multicenter study (ERSPC). Prostate 67:439–446

    Article  PubMed  CAS  Google Scholar 

  • Ruijter ET, van de Kaa CA, Schalken JA, Debruyne FM, Ruiter DJ (1996) Histological grade heterogeneity in multifocal prostate cancer. Biological and clinical implications. J Pathol 180:295–299

    Article  PubMed  CAS  Google Scholar 

  • Sauer CG, Kappeler A, Späth M, Kaden JJ, Michel MS, Mayer D, Bleyl U, Grobholz R (2004) Expression and activity of matrix metalloproteinases-2 and -9 in serum, core needle biopsies and tissue specimens of prostate cancer patients. Virchows Arch 444:518–526

    Article  PubMed  CAS  Google Scholar 

  • Schalken J, Dijkstra S, Baskin-Bey E, van Oort I (2014) Potential utility of cancer-specific biomarkers for assessing response to hormonal treatments in metastatic prostate cancer. Ther Adv Urol 6:245–252 (Review)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Schayek H, Bentov I, Sun S, Plymate SR, Werner H (2010) Progression to metastatic stage in a cellular model of prostate cancer is associated with methylation of the androgen receptor gene and transcriptional suppression of the insulin-like growth factor-I receptor gene. Exp Cell Res 316:1479–1488

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Schröder FH (2009) PSA screening—a review of recent studies. Eur J Cancer 45(Suppl 1):402–404

    Article  PubMed  Google Scholar 

  • Shuman Moss LA, Jensen-Taubman S, Stetler-Stevenson WG (2012) Matrix metalloproteinases: changing roles in tumor progression and metastasis. Am J Pathol 181:1895–1899

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Squire JA, Park PC, Yoshimoto M, Alami J, Williams JL, Evans A, Joshua AM (2011) Prostate cancer as a model system for genetic diversity in tumors. Adv Cancer Res 112:183–216

    Article  PubMed  CAS  Google Scholar 

  • Tachezy R, Hrbacek J, Heracek J, Salakova M, Smahelova J, Ludvikova V, Svec A, Urban M, Hamsikova E (2012) HPV persistence and its oncogenic role in prostate tumors. J Med Virol 84:1636–1645

    Article  PubMed  CAS  Google Scholar 

  • Tamburrino L, Salvianti F, Marchiani S, Pinzani P, Nesi G, Serni S, Forti G, Baldi E (2012) Androgen receptor (AR) expression in prostate cancer and progression of the tumor: lessons from cell lines, animal models and human specimens. Steroids 77:996–1001

    Article  PubMed  CAS  Google Scholar 

  • Tomlins SA, Rhodes DR, Perner S, Dhanasekaran SM, Mehra R, Sun XW, Varambally S, Cao X, Tchinda J, Kuefer R, Lee C, Montie JE, Shah RB, Pienta KJ, Rubin MA, Chinnaiyan AM (2005) Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science 310:644–648

    Article  PubMed  CAS  Google Scholar 

  • Van Buuren S, Oudshoorn CGM (2000) Multivariate Imputation by Chained Equations: MICE V1.0 User’s manual. TNO Report PG/VGZ/00.038. TNO Preventie en Gezondheid, Leiden

  • Vandesompele J, De Preter K, Pattyn F, Poppe B, Van Roy N, De Paepe A, Speleman F (2002) Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol 3:RESEARCH0034

    Article  PubMed  PubMed Central  Google Scholar 

  • Yang B, Bhusari S, Kueck J, Weeratunga P, Wagner J, Leverson G, Huang W, Jarrard DF (2013) Methylation profiling defines an extensive field defect in histologically normal prostate tissues associated with prostate cancer. Neoplasia 15:399–408

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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Acknowledgments

Supported by Ministry of Health, PIO project RFPS-2006-1-339924. “Risk prediction models, biomarkers predictivity, improving equity in cancer screening.” We thank Karin Andersson for reviewing the manuscript. Thanks to all the staff involved for their assistance in running the study.

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Correspondence to Cristina Sani.

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Carozzi, F., Tamburrino, L., Bisanzi, S. et al. Are biomarkers evaluated in biopsy specimens predictive of prostate cancer aggressiveness?. J Cancer Res Clin Oncol 142, 201–212 (2016). https://doi.org/10.1007/s00432-015-2015-1

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  • DOI: https://doi.org/10.1007/s00432-015-2015-1

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