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BACKGROUND: The metastatic potential of a series of prostate cell lines was analysed by measuring motility and invasiveness, and further correlated to the expression of epithelial differentiation markers. METHODS: Invasion and motility were measured using in vitro assays. Immunohistochemistry of cell lines and tissues was used to identify expression of cytokeratins 8 and 1, 5, 10, 14, vimentin, prostate specific antigen, prostate specific membrane antigen, androgen receptor, desmoglein, E-cadherin, beta1 integrin, CD44, hmet, vinculin and actin. RESULTS: Expression of vimentin was the only marker to correlate with motility, no markers correlated to invasion. Lower vimentin expression was observed in cells with low motility (PNT2-C2) and high expression in cells with high motility (P4E6, PNT1a, PC-3). Vimentin expression was not detected in well differentiated tumours, moderately differentiated tumours contained vimentin positive cells (1/9 bone scan negative, 2/5 bone scan positive), but the majority of poorly differentiated cancers (4/11 bone scan negative, 9/14 bone scan positive) and bone metastases (7/8) had high vimentin expression in tumour cells. CONCLUSIONS: Motile prostate cancer cell lines express vimentin. In tissue sections, the presence of vimentin positive tumour cells correlated positively to poorly differentiated cancers and the presence of bone metastases.

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Prostate cancers ability to invade and grow in bone marrow stroma is thought to be due in part to degradative enzymes. The formation of prostate skeletal metastases have been reproduced in vitro by growing co-cultures of prostatic epithelial cells in bone marrow stroma. Expression of urokinase plasminogen activator, matrix metalloproteinase 1 and 7 by prostatic epithelial cells were identified using immunocytochemistry. Also, in vivo tissue sections from human prostatic bone marrow metastases were stained. To establish the role of these enzymes on colony formation, inhibitory antibodies directed against urokinase plasminogen activator, matrix metalloproteinase 1 and matrix metalloproteinase 7 were added into primary prostatic epithelial cells and bone marrow stroma co-cultures. All prostatic epithelial cell cultures stained positively for matrix metalloproteinase 1, matrix metalloproteinase 7 and urokinase plasminogen activator. Generally prostatic epithelial cells derived from malignant tissues showed increased staining in comparison to epithelia derived from non-malignant tissue. In agreement with in vitro co-cultures, the in vivo tissue sections of prostate bone marrow metastases showed positive staining for all three enzymes. Inhibition studies demonstrated that blocking matrix metalloproteinase 1, matrix metalloproteinase 7 and urokinase plasminogen activator function reduced the median epithelial colony area significantly in bone marrow stroma co-cultures in vitro. Using a human ex-vivo model we have shown that matrix metalloproteinase 1, matrix metalloproteinase 7 and urokinase plasminogen activator play an important role in the establishment of prostatic epithelial cells within bone marrow.

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OBJECTIVE: To determine the E-cadherin and beta-catenin expression phenotype in untreated primary prostate cancer and corresponding bone metastases. MATERIALS AND METHODS: Paired bone metastasis and primary prostate specimens were obtained from 14 men with untreated metastatic prostate carcinoma. The tumours were histologically graded by an independent pathologist. Expression of mRNA for E-cadherin and beta-catenin was detected within the tumour cells using in-situ hybridization with a 35S-labelled cDNA probe. The expression of E-cadherin and beta-catenin were graded as uniform, heterogeneous or negative. RESULTS: The mRNA for E-cadherin was expressed in 13 of 14 primary carcinomas and 11 bone metastases; beta-catenin was expressed by 13 and nine, respectively. Of the primary tumours, nine expressed E-cadherin and beta-catenin uniformly; in contrast, all metastases had down-regulated E-cadherin and/or beta-catenin. CONCLUSIONS: The down-regulation of E-cadherin and beta-catenin are a feature of the metastatic phenotype, which may be a significant factor in the genesis of bone metastases. However, this does not appear to be reflected in the expression of these molecules in the primary tumours.

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Parathyroid hormone-related peptide is a regulatory protein implicated in the pathogenesis of bone metastases, particularly in breast carcinoma. Parathyroid hormone-related peptide is widely expressed in primary prostate cancers but there are few reports of its expression in prostatic metastases. The aim of this study was to examine the expression of parathyroid hormone-related peptide and its receptor in matched primary and in bone metastatic tissue from patients with untreated adenocarcinoma of the prostate. Eight-millimetre trephine iliac crest bone biopsies containing metastatic prostate cancer were obtained from 14 patients from whom matched primary tumour tissue was also available. Histological grading was performed by an independent pathologist. The cellular location of mRNA for parathyroid hormone-related peptide and parathyroid hormone-related peptide receptor was identified using in situ hybridization with (35)S-labelled probe. Expression of parathyroid hormone-related peptide and its receptor was described as uniform, heterogenous or negative within the tumour cell population. Parathyroid hormone-related peptide expression was positive in 13 out of 14 primary tumours and in all 14 metastases. Receptor expression was evident in all 14 primaries and 12 out of 14 metastases. Co-expression of parathyroid hormone-related peptide and parathyroid hormone-related peptide receptor was common (13 primary tumours, 12 metastases). The co-expression of parathyroid hormone-related peptide and its receptor suggest that autocrine parathyroid hormone-related peptide mediated stimulation may be a mechanism of escape from normal growth regulatory pathways. The high frequency of parathyroid hormone-related peptide expression in metastases is consistent with a role in the pathogenesis of bone metastases.

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Parathyroid hormone-related peptide (PTHrP) is a regulatory protein associated with cell growth in non-osseous tissues and with osteoclast stimulation in bone. It has been implicated in the pathogenesis of bone metastases, particularly in breast carcinoma. PTHrP is widely expressed in primary prostate cancers, but there are few reports of its expression in prostatic metastases. The aim of this study was to examine the expression of PTHrP in bone metastases from patients with untreated adenocarcinoma of the prostate. Ten bone biopsies containing metastatic deposits of untreated prostatic cancer were identified. These were immunohistochemically stained for PTHrP using a murine monoclonal antibody (PTHLP[Ab1]) and the streptavidin-biotin complex technique. Intensity of staining for PTHrP was graded by two observers. In total, PTHrP expression was positive in 5/10 specimens. This was graded as moderate in four and weak in one. In those specimens with positive staining, the expression varied between cells. There was no obvious association between expression of PTHrP and tumour differentiation. PTHrP is expressed in prostatic bone metastases and may have a role in their pathogenesis and pathophysiology. However, expression is not universal.

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OBJECTIVE: Prostate cancer in bone is generally thought to progress more rapidly than in its primary site, a supposition that is supported by studies of prostate-specific antigen velocity. However, descriptions of proliferative rates in metastases have relied on inferred data from in vitro studies of cell lines derived from metastases. The aim of this study was to determine directly the proliferative rate within bone metastases arising from prostate cancer. PATIENTS AND METHODS: 10 bone biopsies containing metastatic deposits of untreated prostatic cancer were obtained. These were immunohistochemically stained for the Ki-67 protein with the monoclonal antibody MIB-1, using the streptavidin-biotin complex technique. Benign prostatic tissue was used as the control. Using an image analyser, the Ki-67 index (% of cells staining positively) in each specimen was determined. RESULTS: In the 10 specimens the Ki-67 index ranged from 0.15 to 7.82%. Wide overlap was seen between groups of differing tumour differentiation. CONCLUSION: The proliferative rate as determined by the Ki-67 index in bone metastases of prostate cancer is similar to that reported in primary tumours. There does not appear to be a relationship between tumour grade and proliferative index in these specimens.

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OBJECTIVE: To present the results of the staged management of complex entero-urinary fistulae. PATIENTS AND METHODS: Ten patients with complex entero-urinary fistulae were reviewed; all patients were referred to a national intestinal failure unit after failed treatment in other centres. Each patient was treated in three stages. The acute stage involved proximal defunctioning and distal drainage of both the gastrointestinal and urinary tracts to isolate the fistula, together with the eradication of sepsis. The recovery stage involved total parenteral nutrition, organ support, radiological planning of surgical reconstruction and intensive nursing. The reconstructive stage followed when the patient was stable, nutritionally replenished and intra-abdominal sepsis was controlled. Surgery was undertaken jointly by urological and gastrointestinal surgeons. RESULTS: The fistulae were treated successfully in all patients, with functional restoration in four, and/or diversion of the gastrointestinal and urological tracts in six. The mean (range) time to reconstruction was 5 (1-20) months. There were no postoperative deaths. CONCLUSION: A staged multidisciplinary approach with delayed reconstruction can achieve a successful outcome in the management of complex entero-urinary fistulae.

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OBJECTIVE: To determine whether the calcium-dependent cell adhesion molecule E-cadherin is expressed in metastatic deposits of prostate cancer in bone. PATIENTS AND METHODS: Ten bone biopsies containing metastatic deposits of untreated prostatic cancer were obtained and immunohistochemically stained for E-cadherin with the monoclonal antibody HECD-1, using the streptavidin-biotin complex technique. Benign prostatic tissue was used as the control. RESULTS: Of the 10 specimens, nine showed positive expression of E-cadherin, graded as strong in four. E-cadherin expression was strongest in well-differentiated metastases and decreased with increasing tumour grade. In some specimens there were mixed patterns of expression. CONCLUSION: E-cadherin is strongly expressed in prostatic bone metastases and the degree of expression appears to reflect local tumour grade. This suggests that loss of E-cadherin expression may not be critically linked to metastatic potential.

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Apoptosis and its augmentation by androgen withdrawal is an important event in the testis. In other tissues apoptosis is regulated by genes belonging to the bcl-2 family. However, little is known about these pathways in the human testes. Human testes were obtained from patients with prostate cancer, undergoing orchidectomy for permanent androgen ablative treatment. The patients were either untreated or had previously received short- or long-term anti-androgen therapy by cyproterone acetate or GnRH agonist (goserelin). In comparison with untreated patients, testicular testosterone concentrations were reduced by 83% in patients treated with cyproterone acetate and by 99% in patients treated with goserelin. Apoptotic cells were identified in tissue sections by in-situ end labelling of fragmented DNA. The expression of Bcl-2, Bcl-xl, Bax, p53 and poly(ADP) ribose polymerase (PARP) was demonstrated in tissue extracts by Western blotting. Apoptotic germ cells were present in the spermatogenic epithelium of untreated patients and patients who received short-term anti-androgen treatment. There were few or no apoptotic cells in the seminiferous tubules following long-term anti-androgen treatment. Following short-term treatment, the concentrations of the apoptosis-related proteins examined did not change. However, in the long-term treated testes, Bcl-xl and PARP expression declined, Bax and p53 protein concentrations were unchanged, and Bcl-2 was up-regulated. In conclusion, apoptosis occurs in spermatogenic cells of the human testis and may contribute to the regulation of germ cell populations. The apoptosis-related gene products which have been described in other tissues are present in the human testis and are modulated by androgenic stimuli.

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Haematuria is a common symptom and sign that may be encountered in almost all medical specialties. The possibility that haematuria may signal an underlying malignancy means that it must not be ignored. This article outlines the diagnostic procedures relevant to haematuria, such that serious causes of bleeding are identified and treatment may be initiated.

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