Correlation of vascular endothelial growth factor expression with fibroblast growth factor-8 expression and clinico-pathologic parameters in human prostate cancer.

Vascular endothelial growth factor (VEGF) mediates neo-angiogenesis during tumour progression and is known to cooperate with the fibroblast growth factor (FGF) system to facilitate angiogenesis in a synergistic manner. In view of this, we have investigated VEGF expression in 67 cases of prostate cancer previously characterized for fibroblast growth factor-8 (FGF-8) expression. Cytoplasmic VEGF staining was detected in malignant cells in 45 out of 67 cases. Cytoplasmic staining was found in adjacent stromal cells in 32 cases, being particularly strong around nests of invasive tumour. Positive VEGF immunoreactivity in benign glands was restricted to basal epithelium. A significant association was observed between tumour VEGF and FGF-8 expression (P = 0.004). We identified increased VEGF immunoreactivity in both malignant epithelium and adjacent stroma and both were found to be significantly associated with high tumour stage (P = 0.0047 and P = 0.0002, respectively). VEGF expression also correlated with increased serum PSA levels (P = 0.01). Among positively stained tumours, VEGF expression showed a significant association with Gleason score (P = 0.04). Cases showing positive VEGF immunoreactivity in the stroma had a significantly reduced survival rate compared to those with negative staining (P = 0.037). Cases with tumours expressing both FGF-8 in the malignant epithelium and VEGF in the adjacent stroma had a significantly worse survival rate than those with tumours negative for both, or only expressing one of the two growth factors (P = 0.029). Cox multivariate regression analysis of survival demonstrated that stromal VEGF and tumour stage were the most significant independent predictors of survival. In conclusion, we report for the first time a correlation of both tumour and stromal VEGF expression in prostate cancer with clinical parameters as well as its correlation to FGF-8 expression.

Focal changes in nerve, muscle and connective tissue in normal and unstable human bladder.

OBJECTIVE: To compare and quantify, in a morphological study, the changes that occur in the connective tissue elements (elastin and collagen), muscle fibre diameters and nerve densities between normal, idiopathic and neuropathic bladders. MATERIALS AND METHODS: Bladder tissue was obtained from 27 patients undergoing cystectomy for carcinoma, from 12 with idiopathic instability and from seven neuropathic patients who were undergoing ileocystoplasty. A combination of histochemical and immunohistochemical techniques were used to detect detrusor muscle, connective tissue and nerve profiles in the bladder tissue. RESULTS: In both idiopathic and neuropathic bladder tissue the structural changes were highly punctate. From the density of nerve profiles, three areas were defined: (i) apparently unaffected normal fascicles with a high density of nerves, no hypertrophy of the muscle and no infiltration of elastin and collagen. The nerve density in these areas was similar to that in normal bladder tissue. (ii) Fascicles with a low density of nerve profiles, muscle hypertrophy but no connective tissue infiltration. (iii) Areas with few nerve profiles, muscle hypertrophy and extensive elastin and collagen infiltration within the fascicles. The mean (sem) density of nerve profiles in control tissue was 752 (53) nerves/mm2 and in the idiopathic bladders was 905 (91), 81 (20) and 74 (38) nerves/mm2 in the three defined areas, respectively. In the neuropathic tissues the nerve profile densities were 672 (249), 57 (23) and 37 (28) nerves/mm2, respectively. Fibre diameter, elastin and collagen content and nerve density were measured in normal and unstable bladder tissue using these three defined areas. The mean (sem) fibre diameter was 6.81 (0.52) in normal bladder; in idiopathic bladder tissue the fibre diameters in the three areas were 6.72 (0.62), 7.06 (0.62) and 7.34 (1.15) micrometer, respectively, and in neuropathic bladders were 6.75 (0.62), 8.24 (0.62) and 9.35 (0.62) micrometer, respectively. The relative areas of elastin were 0.79 (0.70), 0.56 (0.45) and 18.3 (4.1)% for the control, normal and affected areas of the neuropathic bladders, respectively, and the relative areas of collagen were 3.5 (1.3), 6.15 (3.6) and 15.7 (5. 0)%, respectively. The pattern was similar in idiopathic bladders. CONCLUSION: These observations suggest that the primary defect in the idiopathic and neuropathic bladders is a loss of nerves accompanied by a hypertrophy of the cells. These changes may continue with further hypertrophy of the cells and an increased production of elastin and collagen within the muscle fascicles.

bcl-2 overexpression combined with p53 protein accumulation correlates with hormone-refractory prostate cancer.

Seventy-seven men with histologically proven and newly diagnosed prostate cancer we investigated for the presence of bcl-2 protein overexpression and p53 protein accumulation 1 immunohistochemistry. Forty-five men had evidence of locally advanced and metastatic disease and we treated by means of hormone manipulation. Twenty-eight patients either failed to respond to initial hormone manipulation or relapsed within 37 months from diagnosis (median 20 months). Of the 77 cancers, 37 (48% showed bcl-2 overexpression at diagnosis. Twenty-seven of those were treated with androgen ablation and 2 (74%) had hormone-refractory disease (P = 0.0128). Twenty-three of 77 men (29.8%) had nuclear staining for p53 protein. Twenty-one of those were treated with hormone manipulation and 14 (66.6%) showed hormone resistance (P = 0.0012). Seventeen patients had both bcl-2 overexpression and p53 protein accumulation, 16 of whom were hormonally treated, with 13 (81.2%) having hormone-refractory disease (P < 0.0001). These findings suggest that the combined detection of p53 protein accumulation and bcl-2 overexpression may be useful in predicting hormone resistance in prostate cancer. By deregulating programmed cell death, alteration in these genes may prevent patients from responding to androgen ablation, or allow them to escape hormonal control of the disease.

P53 and Ki-67 immunoreactivity in human prostate cancer and benign hyperplasia.

Mutation of the p53 gene is one of the commonest genetic abnormalities found in solid human tumours. This gene is probably concerned with the control of cellular proliferation and in view of this we carried out a study of human prostate cancer and benign prostatic hyperplasia, comparing the expression of mutated p53 with measurement of growth fractions as assessed by staining with Ki-67. A series of 29 patients with prostate cancer (CaP) were compared with 34 men with benign hyperplasia (BPH); 22 of 29 prostate cancers (76%) contained Ki-67 immunoreactivity compared with 10 of 34 (29%) BPH. With respect to p53 staining, significantly more prostate cancers (17%) were stained than BPH (0%). The mean Ki-67 score in cancers positive for p53 (4.3%) was greater than that found in cancers negative for p53 (1.2%), but no statistically significant relationship was found between tumour grade and Ki-67 staining. The use of Ki-67 and p53 staining may allow identification of tumours with a higher rate of cell growth and may permit development of prognostic factors.

p53, c-erbB-2 and the epidermal growth factor receptor in the benign and malignant prostate.

Expression of the p53, the epidermal growth factor receptor (c-erbB-1) and c-erbB-2 protein was studied in 34 men with benign prostatic hyperplasia and 29 men with locally advanced prostate cancer by means of an immuno-histochemical method. Strong staining for p53 was found in five of 29 prostate cancers (17%; mean 21% +/- 7% of malignant cells stained in the positive tumours), but no staining was found in benign prostatic hyperplasia (p less than 0.05). On the other hand, the epithelium in benign glands was stained positively for c-erbB-2 in 18% (6/34) and for the epidermal growth factor receptor in 88% (30/34); whereas malignant epithelium stained strongly for c-erbB-2 in 21% (6/29) and for the epidermal growth factor receptor in only 17% (5/29). Prostate cancer was associated with a significant decrease in epidermal growth factor receptor staining (p less than 0.0001) and a significant increase in p53 staining (p less than 0.05). Most of the tumours were advanced and no significant relationship was observed between tumour stage and grade and expression of p53, the epidermal growth factor receptor or c-erbB-2. These findings demonstrate that altered expression of the epidermal growth factor receptor and p53 protein occurs in prostate cancer, but were not associated with other features of prognostic importance such as stage or grade.

Histochemical study of lectin binding in neoplastic and non-neoplastic urothelium.

A histochemical study of lectin binding was performed to assess staining with lectins and, therefore, the expression of complex carbohydrates in human neoplastic urothelium. Forty-seven patients with transitional cell carcinoma of the bladder and six controls were studied. Cryostat sections were stained with a panel of 10 biotinylated lectins by means of the avidin-biotin-peroxidase technique. Sixteen tumours were also studied after conventional formalin fixation and paraffin embedding. In general, staining by lectins of tumours was more intense than staining of control urothelium and staining of tumours invading bladder muscle was greater than that of superficial tumours (both P less than 0.001). A small but statistically significant diminution of staining was observed after formalin fixation and paraffin embedding (P less than 0.05). Four lectins--Bandeiraea simplicifolia (P less than 0.01), Vicia villosa (P less than 0.01), peanut agglutinin (P less than 0.001) and soyabean agglutinin (P less than 0.001) stained invasive tumours more frequently than superficial tumours in frozen sections. Thus, increased binding of certain lectins was found in human transitional cell tumours and correlated with muscle invasion and poor differentiation.