Marinus A. Noordzij

Androgen-independent growth is induced by neuropeptides in human prostate cancer cell lines.

Androgen‐independent growth leads to progressive prostate cancer after androgen‐ablation therapy. This may be caused by altered specificity of the androgen receptor (AR), by ligand‐independent stimulation of the AR, or by paracrine growth modulation by neuropeptides secreted by neuroendocrine (NE) cells.

PROGNOSTIC VALUE OF CELL CYCLE PROTEINS p27kip1 AND MIB-1, AND THE CELL ADHESION PROTEIN CD44s IN SURGICALLY TREATED PATIENTS WITH PROSTATE CANCER

PURPOSE Molecular tissue markers may give the clinician additional information about patients with prostate cancer at risk for treatment failure after retropubic radical prostatectomy. We substantiate the prognostic value of 3 tissue markers, the cell cycle proteins p27(kip1) and MIB-1, and the cell adhesion protein CD44s, in addition to more conventional pathological prognosticators in an historical (before prostate specific antigen) cohort of patients with prostate cancer. MATERIALS AND METHODS Representative tumor sections from 92 patients who underwent retropubic radical prostatectomy were immunohistochemically stained with antibodies against p27(kip1), MIB-1 (Ki-67) and CD44s, and assessed in a semiquantitative manner. Gleason score and pathological tumor stage were recorded. All variables were correlated with clinical progression and disease specific survival on univariate and multivariate analyses. RESULTS On univariate analysis low (less than 50%) p27(kip1), high (10% or greater) MIB-1 and loss of CD44s expression were significantly associated with clinical outcome parameters, although MIB-1 did not reach statistical significance for disease specific survival. All 3 molecules were highly correlated with Gleason score and pathological tumor stage. Multivariate analysis showed that low p27kip1 was independent of grade and stage in predicting clinical recurrence (p <0.001) and disease specific survival (p = 0.045), while loss of CD44s was an additional independent prognostic factor for clinical recurrence (p = 0.02). CONCLUSIONS Reduced p27(kip1) expression is an independent predictor of poor outcome in prostate cancer, while MIB-1 is not. Decreased expression of CD44s yields additional information in predicting clinical recurrence. These tissue markers may identify patients at risk for disease recurrence after retropubic radical prostatectomy who may benefit from adjuvant therapy.

Expression and Prognostic Value of Epidermal Growth Factor Receptor, Transforming Growth Factor-, and c-erb B-2 in Nephroblastoma

Wilms tumor is one of the most common solid tumors in children. A transforming growth factor‐α (TGF‐α)/epidermal growth factor receptor (EGF‐R) autocrine loop plays an important role in tumor growth. Abnormal expression of TGF‐α, EGF‐R and c‐erb B‐2 has been demonstrated in several human malignancies.

Neuroendocrine cells in the normal, hyperplastic and neoplastic prostate

Neuroendocrine cells can be demonstrated in normal, hyperplastic and neoplastic prostatic tissues. The products secreted by these cells can be used as tissue and/or serum markers but may also have biological effects. Neuroendocrine cells in prostate cancer most probably do not contain the androgen receptor and are therefore primarily androgen independent. Some of the neuropeptides secreted by the neuroendocrine cells may act as growth factor by activation of membrane receptors in an autocrine-paracrine fashion or by ligand-independent activation of the androgen receptor in neighboring non-neuroendocrine cells. Evidence is accumulating from experiments with tumor models that neuropeptides indeed can influence the growth of prostatic tumor cells. Future research on neuroendocrine differentiation may answer some questions concerning the biological behavior of clinical prostatic tumors.

Decreased expression of cd44 in metastatic prostate cancer

Decreased expression of CD44 is an independent prognostic marker for surgically treated prostate cancer. To investigate immunohistochemically defined CD44 expression in primary and metastatic prostate cancer, 2 groups of patients undergoing radical prostatectomy for clinically localized prostate cancer were studied. (1) pN1 group: 23 patients, finally staged pN1, of whom the radical prostatectomy specimen and the lymph nodes were investigated to establish a correlation between CD44 expression in the concurrently resected primaries and metastases; (2) pN0 group: 23 patients with pN0 disease matched for pT stage and Gleason sum score with the pN1 patients. Progression rates based on serum prostate‐specific antigen (PSA) levels could be determined in 42 of these 46 patients. In addition, 28 distant metastases were studied. A CD44 score of < 10% was found in 22 of the 23 lymph node metastases (96%) and in 20 of the corresponding radical prostatectomies. In the pN0 group this was observed in only 6 out of 23 specimens. In most of the distant metastases CD44 scores were < 10%. Patients with pN0 disease and > 10% CD44‐positive tumor cells had a significantly better prognosis than the other patients who were not significantly different from each other. CD44 expression is thus strongly reduced in prostate cancer metastases as well as in the corresponding primary tumors. This reduction may be used to predict the N stage clinically, provided that CD44 scores can be determined reliably on preoperative biopsy specimens. Int. J. Cancer (Pred. Oncol.) 84:478–483, 1999.

The prognostic significance of apoptosis-associated proteins BCL-2, BAX and BCL-X in clinical nephroblastoma

Apoptotic cell death represents an important mechanism for the precise regulation of cell numbers in normal tissues. Various apoptosis-associated regulatory proteins, such as Bcl-2, Bax and Bcl-X, may contribute to the rate of apoptosis in neoplasia. The present study was performed to evaluate the prognostic value of these molecules in a group of 61 Wilms’ tumours of chemotherapeutically pre-treated patients using an immunohistochemical approach. Generally, Bcl-2, Bax and for Bcl-XS/L were expressed in the blastemal and epithelial components of Wilms’ tumour. Immunoreactive blastema cells were found in 53%, 41% and 38% of tumours for Bcl-2, Bax and for Bcl-XS/L, respectively. An increased expression of Bcl-2 was observed in the blastemal component of increasing pathological stages. In contrast, a gradual decline of Bax expression was observed in the blastemal component of tumours with increasing pathological stages. Also blastemal Bcl-XS/L expression decreased with stage. Univariate analysis showed that blastemal Bcl-2 expression and the Bcl-2/Bax ratio were indicative for clinical progression, whereas epithelial staining was of no prognostic value. Multivariate analysis showed that blastemal Bcl-2 expression is an independent prognostic marker for clinical progression besides stage. These findings demonstrate that alterations of the Bcl-2/Bax balance may influence the clinical outcome of Wilms’ tumour patients by deregulation of programmed cell death.

THE PROGNOSTIC VALUE OF PRETREATMENT EXPRESSION OF ANDROGEN RECEPTOR AND BCL-2 IN HORMONALLY TREATED PROSTATE CANCER PATIENTS

PURPOSE We determined the prognostic value of oncoprotein bcl-2 and androgen receptor expression in pretreatment transurethral resection specimens of hormonally treated prostate cancer patients. MATERIALS AND METHODS A total of 68 pretreatment transurethral resection specimens, 30 radical prostatectomy specimens and 21 palliative transurethral resection specimens with androgen independent prostate cancer was stained with a monoclonal antibody against bcl-2. Androgen receptor immunohistochemistry was performed on pretreatment transurethral resection specimens only. Results were scored semiquantitatively and were correlated with tumor stage and grade and with the occurrence of clinical progression or tumor related death. RESULTS Bcl-2 expression by adenocarcinoma cells was found in 32, 17 and 24% of pretreatment transurethral resection, radical prostatectomy and palliative transurethral resection specimens, respectively. The bcl-2 scores did not correlate with tumor stage or grade. Androgen receptor was expressed in 88% of pretreatment transurethral resection specimens. Androgen receptor scores were marginally related to tumor grade, but not to tumor stage. A prognostic value of bcl-2 or androgen receptor in pretreatment transurethral resection specimens was not found. When a combined bcl-2/androgen receptor score was used, this parameter was an independent prognostic marker to predict clinical progression with Gleason grade and stage classification. Gleason grade was the only independent prognostic marker to predict tumor related death. CONCLUSIONS The expression of bcl-2 and androgen receptor in pretreatment prostate cancer specimens is not related to the prognosis of hormonally treated prostate cancer. Bcl-2 expression is not increased in endocrine therapy resistant prostate cancer. Surprisingly, a combined bcl-2/androgen receptor score acts as an independent prognosticator for clinical progression.

The genetic make-up of renal cell tumors.

Abstract Recent developments in (molecular) genetics have led to a better understanding of renal tumor biology. The current knowledge of the genetics of benign as well as malignant renal tumors is discussed briefly. This knowledge may, in the near future, be used to more accurately diagnose these tumors and also to optimalize individually based therapy.

Expression And Prognostic Value Of CD44 Isoforms In Nephroblastoma (Wilms Tumor)

PURPOSE CD44 is a group of transmembranous glycoproteins formed by alternative splicing of a single messenger RNA. An abnormal pattern of CD44 expression has been demonstrated in several human malignancies. We evaluate the prognostic value of standard CD44 (CD44s) and some of its isoforms in treating clinical Wilms tumor. MATERIALS AND METHODS The immunohistochemical expression of CD44 isoforms was studied in paraffin material of 61 clinical Wilms tumors. Patients were treated preoperatively with chemotherapy and mean followup was 5.7 years. RESULTS Generally CD44s, CD44v5 and CD44v10 were expressed in normal kidney tissues and at variable levels in the 3 cell types of Wilms tumor (blastemal, epithelial and stromal). No CD44v6 expression was found neither in normal kidney or in tumor tissue. CD44s, CD44v5 and CD44v10 epithelial expression gradually decreased from stage T1 to T3. By contrast the percentage of CD44 positive cells in the blastemal component significantly increased from T1 to T3. CD44 immunoreactive blastema cells were found in 62%, 44% and 41% for CD44s, CD44v5 and CD44v10, respectively. Blastemal expression of CD44s and CD44v5 statistically significantly correlated with clinicopathological stage. Univariate and multivariate analyses showed that blastemal CD44v5 expression was indicative of poor prognosis. CONCLUSIONS Increased expression of CD44v5 in the blastemal part of Wilms tumor correlated with tumor stage, clinical progression and tumor related death. Therefore, blastemal CD44v5 expression may be of value in identifying patients with a high propensity for distant metastases. These patients might benefit from adjuvant chemotherapy and/or radiotherapy.