Sub theme 3.8
Clinical and experimental aspects of urological tumors

Goals of research: general outline
Scientific achievements
Future plans: special goals and approach
Running projects
Associated staff

Goals of research: general outline

The research program at the department of Urology and Pathology with regard to Molecular Medicine involves the basic, clinical, and epidemiological aspects of prostate and bladder cancer. Next to the latter, support is given to the research on testicular cancer and fertility, defined predominantly within the department of Pathology.

In prostate cancer, the ontogenesis, growth and differentiation of cancer is studied by genomic, proteomic, and metabolomic techniques in a unique set of in vitro and in vivo model systems as well as an extensive set of biomaterials (serum, plasma, urine, tissue biopsies, radical prostatectomy specimens) with long term follow-up obtained from patients in all disease stages. A special interest lies in:

  • the research on androgen regulation and genetics, linked to the department of Pathology, Prof J Trapman, for the mechanism of androgen independency and the discovery of genetic changes responsible for prostate cancer initiation.
  • Novel genomic and proteomic biomarkers for the diagnosis and prognosis of prostate cancer
  • The research on cancer stem cells headed by Dr GJLH van Leenders, department of Pathology.
  • The development of model systems in cell lines and xenografts, Dr W van Weerden, department of Urology, for basic research and the development of new imaging methods (together with Prof M de Jong, department of Nuclear Medicine) and novel drug evaluation.

The department of Urology is running the European Randomised Study for Screening of Prostate Cancer (ERSPC), an epidemiologic study in 260.000 men in eight European countries, and the PRIAS study on active surveillance of detected cancers. The ERSPC program is coordinated internationally by Prof F Schroder, while PRIAS and ERSPC are conducted by Dr M Roobol in Rotterdam. From this study, research questions are formulated regarding the variable biologic course of prostate cancer. Emphasis lays on the identification and validation of new diagnostic and prognostic biomarkers in patient derived biomaterials by proteomic methods together with Dr T Luider, department of Neurology, and Dr R van Schaik, department of Clinical Chemistry.

A special activity has been developed in the field of experimental therapeutics by adenoviral vector based oncolytic gene therapy. The department of Urology is participating in the European FP6 consortium GIANT, and is preparing a clinical trial together with the department of Medical Oncology supported by ZonMW (coordinated by Dr. E Schenk-Braat). Immunologic aspects as well as gene delivery are analysed in preclinical models and patient derived biomaterials.

The department of urology is participating in, or coordinating, various national and international consortia on the development of biomarkers and therapeutic targets in Europe (PRIMA, PMARK, ProspeR, CANCURE, PRONEST, GLYCOPRO). It is coordinating the Dutch translational CTMM program on molecular medicine (PCMM) that focuses on new imaging methods and diagnostics.

For bladder cancer, basic research on the growth and differentiation towards aggressive invasive or non-invasive cancers is conducted by Prof E Zwarthoff, department of Pathology. Emphasis is on the development validation of genomic urine markers from well documented samples that are derived from the clinic as well as from a population based screening study in Rotterdam. The project group is participating in a FP6 project on diagnostics for bladder cancer.

Scientific achievements

Prostate cancer (Bangma, Jenster, Van Leenders)

During the last five years the research groups have created a large and well defined unique biobank combining well preserved serum, prostate biopsies, operative samples, and urine with long term clinical follow up. Analyses based on these samples generated a list of potential and patentable genomic and proteomic diagnostic and prognostic markers. The cell lines and xenografts generated in the department of Urology have been utilized to identify novel genes and proteins expressed in stem cell subpopulations and novel biomarkers secreted into the blood stream by the cancer cells. For this, cutting edge technologies (Solexa sequencing, Exon arrays, SNP arrays, protein arrays, mass spectrometry, tissue microarrays) have been implemented. Various novel genes, predominantly expressed in stem cell subpopulations and the role of the HGF/cMET pathway in the stem cell phenotype have been identified. Prostate cancer-secreted vesicles (exosomes) have been identified as important serum and urine biomarker ‘treasure chests’ from which both protein and RNA markers can be extracted. Also the role of FOXF2 in stromal-epithelial crosstalk in the developing prostate and the expression of small noncoding RNAs have been studied.

Novel prostate cancer cell line models have been established by long-term culturing cells in androgen-depleted medium, mimicking the changes observed in patients undergoing androgen-ablation therapy. These cell lines are being investigated for molecular changes, causing the transition to an androgen-independent growth pattern.

The prostate cancer research groups at the Erasmus MC have been very successful in establishing and extending funded networks of clinical and preclinical scientists. See also 3.1.2., Solid Tumors/postate cancer (Trapman, van Leenders).

Bladder cancer (Zwarthoff, Bangma)

See subtheme 3.1.3, Solid tumors/Bladder cancer. 

Future plans: special goals and approach

Prostate cancer (Bangma, Jenster, Van Leenders)

The focus in the next few years will be on (i) identifying novel genes and pathways involved in the initiation and progression of prostate cancer, (ii) selection and characterization of the prostate cancer stem cell population, (iii) development of new cell line model systems for imaging and studying metastasis, (iv) identification and validation of novel biomarkers, and (v) running a clinical trial on oncolytic adenoviruses. Fundamental to all these research efforts are the ongoing collection of patient samples and the development and implementation of state of the art technologies.

Using Exon and SNP array data in combination with Solexa paired-end sequencing, we aim at identifying novel fusion genes, gene deletions, cancer-related splice variants and aberrant promoter usage. Also a strong focus will be on the expression and processing of small noncoding RNAs such snRNAs and miRNAs.

Research on our novel markers for immature tumor-initiating cells will be continued to determine their specificity for this cell population. Whether the HGF/cMET pathway is a therapeutic target for prostate cancer treatment will be further studied.

Important cell line models for prostate cancer are being stably tagged by fluorescent proteins and bioluminescent enzymes for studying migration and metastasis in living animals. This will allow following the in vivo effects of manipulating the genes and pathways we want to study. Using our extensive biobanks, the latest MS technologies (MRM, GC-MS) are being implemented to identify and validate novel protein and metabolite biomarkers in serum and urine. See also 3.1.2., Solid Tumors/postate cancer (Trapman, van Leenders).

Bladder cancer (Zwarthoff, Bangma)

See subtheme 3.3, Solid tumors/Bladder cancer.

Most recent publications

1.      Screening and prostate-cancer mortality in a randomized European study. Schröder FH, Hugosson J, Roobol MJ, Tammela TL, Ciatto S, Nelen V, Kwiatkowski M, Lujan M, Lilja H, Zappa M, Denis LJ, Recker F, Berenguer A, Määttänen L, Bangma CH, Aus G, Villers A, Rebillard X, van der Kwast T, Blijenberg BG, Moss SM, de Koning HJ, Auvinen A; ERSPC Investigators. N Engl J Med. 2009 Mar 26;360(13):1320-8.

2.      An activating mutation in AKT1 in human prostate cancer. Boormans JL, Hermans KG, van Leenders GJ, Trapman J, Verhagen PC. Int J Cancer. 2008 Dec 1;123(11):2725-6

3.      The development of multiple bladder tumour recurrences in relation to the FGFR3 mutation status of the primary tumour. Kompier LC, van der Aa MN, Lurkin I, Vermeij M, Kirkels WJ, Bangma CH, van der Kwast TH, Zwarthoff EC. J Pathol. 2009 May;218(1):104-12.

4.      Exosomal secretion of cytoplasmic prostate cancer xenograft-derived proteins. Jansen FH, Krijgsveld J, van Rijswijk A, van den Bemd GJ, van den Berg MS, van Weerden WM, Willemsen R, Dekker LJ, Luider TM, Jenster G. Mol Cell Proteomics. 2009 Jun;8(6):1192-205

5.      Human xenograft models as useful tools to assess the potential of novel therapeutics in prostate cancer. van Weerden WM, Bangma C, de Wit R. Br J Cancer. 2009 Jan 13;100(1):13-8. Epub 2008 Dec 16.

6.      Screening for Prostate Cancer in 2008 II: The Importance of Molecular Subforms of Prostate-Specific Antigen and Tissue Kallikreins. Jansen FH, Roobol M, Jenster G, Schröder FH, Bangma CH. Eur Urol. 2008 Nov 29

7.      Truncated ETV1, fused to novel tissue-specific genes, and full-length ETV1 in prostate cancer. Hermans KG, van der Korput HA, van Marion R, van de Wijngaart DJ, Ziel-van der Made A, Dits NF, Boormans JL, van der Kwast TH, van Dekken H, Bangma CH, Korsten H, Kraaij R, Jenster G, Trapman J. Cancer Res. 2008 Sep 15;68(18):7541-9.

8.      Two unique novel prostate-specific and androgen-regulated fusion partners of ETV4 in prostate cancer. Hermans KG, Bressers AA, van der Korput HA, Dits NF, Jenster G, Trapman J. Cancer Res. 2008 May 1;68(9):3094-8

9.      Gleason score 7 screen-detected prostate cancers initially managed expectantly: outcomes in 50 men..van den Bergh RC, Roemeling S, Roobol MJ, Aus G, Hugosson J, Rannikko AS, Tammela TL, Bangma CH, Schröder FH. BJU Int. 2009 Jan 9

10.  Mass spectrometric identification of human prostate cancer-derived proteins in serum of xenograft-bearing mice. van den Bemd GJ, Krijgsveld J, Luider TM, van Rijswijk AL, Demmers JA, Jenster G. Mol Cell Proteomics. 2006 Oct;5(10):1830-9.