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ABSTRACT: 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.
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.
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.
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.
The Journal of Urology 09/2002; 168(2):681-6. · 3.75 Impact Factor
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ABSTRACT: Neuroendocrine (NE) cells are androgen-independent cells and secrete growth-modulating peptide hormones via a regulated secretory pathway (RSP). We studied NE differentiation after long-term androgen withdrawal in the androgen-dependent human prostate cancer xenograft PC-310.
Tumor-bearing nude mice were killed at 0, 2, 5, 7, 14, 21, 47, 84, and 154 days after castration. The half-life of the PC-310 tumor was 10 days, with a stable residual tumor volume of 30--40% after 21 days and longer periods of androgen deprivation.
Proliferative activity and prostate-specific antigen serum levels decreased to zero after castration, whereas cell-cycle arrest was manifested by increased p27(kip1) expression. A temporary downregulation of androgen receptor (AR) expression was noted after androgen deprivation. The expression of chromogranin A, secretogranin III, and secretogranin V (7B2) increased 5 days after castration and later. Subsequently, pro-hormone convertase 1 and peptidyl alpha--amidating monooxygenase as well as vascular endothelial growth factor were expressed from 7 days after castration on. Finally, such growth factors as gastrin-releasing peptide and serotonin were expressed in a small part of the NE cells 21 days after castration, but strong expression was induced late during androgen deprivation, that is, 84 and 154 days after castration, respectively.
Androgen deprivation of the NE-differentiated PC-310 model induced the formation of NE-differentiated AR(minus sign) and non-NE AR(+) tumor residues. The NE-differentiated cells actively produced growth factors via an RSP that may lead to hormone-refractory disease. The dormant non-NE AR(+) tumor cells were shown to remain androgen sensitive even after long-term androgen deprivation. In the PC-310 xenograft, time-dependent NE differentiation and subsequent maturation were induced after androgen depletion. The androgen-dependent PC-310 xenograft model constitutes an excellent model for studying the role of NE cells in the progression of clinical prostate cancer.
The Prostate 04/2002; 50(4):203-15. · 3.48 Impact Factor
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Mazen A. Ghanem M.D,
Ph.D. Theodorus H. Van Der Kwast M.D,
Jan C. Den Hollander M.D,
Mondastri K. Sudaryo M.D,
Rejiv B. Mathoera M.D,
Marry M. Van den Heuvel M.D,
Ph.D. Marinus A. Noordzij M.D,
Ph.D. Rien J. M. Nijman M.D,
Gert J. van Steenbrugge Ph.D,
Mazen A. Ghanem,
Theodorus H. Van Der Kwast,
Jan C. Den Hollander,
Mondastri K. Sudaryo,
Rejiv B. Mathoera,
Marry M. Van den Heuvel, Marinus A. Noordzij,
Rien J. M. Nijman,
Gert J. van Steenbrugge
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ABSTRACT: BACKGROUND
Wilms tumor is one of the most common solid tumors in children. A transforming growth factor- (TGF-)/epidermal growth factor receptor (EGF-R) autocrine loop plays an important role in tumor growth. Abnormal expression of TGF-, EGF-R and c-erb B-2 has been demonstrated in several human malignancies.METHODS
The immunohistochemical expression of TGF-, EGF-R, and c-erb B-2 was studied in paraffin material of 62 clinical Wilms tumors. Patients had a mean follow-up of 5.7 years.RESULTSGenerally, TGF-, EGF-R, and c-erb B-2 were expressed in tissue of the normal kidney and at variable levels in the three cell types of Wilms tumor, i.e., blastemal, epithelial, and stromal cells. Immunoreactive blastema cells were found in 48%, 44%, and 34% of tumors for TGF-, EGF-R, and c-erb B-2, respectively. It was found that TGF-, EGF-R, and c-erb B-2 blastemal and epithelial expression gradually increased from T1 to T3. The blastemal expression of TGF- was statistically significantly correlated with clinicopathologic stages. Both univariate and multivariate analysis showed that blastemal TGF- expression was indicative for clinical progression, but neither blastemal TGF-, nor EGF-R or c-erb B-2 expression correlated with patients survival. Epithelial staining was of no prognostic value. The simultaneous expression of TGF-/EGF-R was indicative for clinical progression at univariate level.CONCLUSIONS
Increased expression of TGF- in the blastemal part of Wilms tumor correlated with tumor classification and clinical progression. These findings suggest that significant expression of TGF- and EGF-R may play a role in promoting transformation and/or proliferation of Wilms tumor, perhaps by an autocrine mechanism. Therefore, their expression may be of value in identifying patients at high risk of tumor recurrence. Cancer 2001;92:3120–9. © 2001 American Cancer Society.
Cancer 12/2001; 92(12):3120 - 3129. · 4.77 Impact Factor
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ABSTRACT: 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. © 1999 Wiley-Liss, Inc.
International Journal of Cancer 10/1999; 84(5):478 - 483. · 5.44 Impact Factor
