Summary Prostatic adenocarcinoma commonly metastasizes to bone. Unlike most other bony secondaries, the majority of skeletal prostatic metastases are osteoblastic rather than osteolytic i nature. Several growth factors which are known to stimulate bone formation are expressed in benign and malignant prostate cells. bi none has been specifically linked to osteoscierotic metastases. Bone morphogenetic proteins (BMPs) induce ectopic bone formation in vivo. We have reported previously that BMP-6 mRNA and protein are expressed in the majority of primary prostatic carcinomas with established skeletal metastases but rarely in clinically organ-confined tumours. This study examines the expression of BMP-6 mRNA in matched prostatic primary and secondary bony lesions and in isolated skeletal metastases from prostatic adenocarcinomas, as well as other common human malignancies, by in situ hybridization. BMP-6 mRNA was detected in 11 out of 13 bone metastases from prostate carcinoma and in three paired samples of primary prostate carcinoma and matching skeletal metastasis. Weak signals for BMP-6 were also present in 5 out of 17 skeletal deposits from non-prostatic malignancies. BMP-6 mRNA appears to be strongly expressed in prostatic adenocarcinomas, both in the primary tumour and in bone metastases. It is also expressed, though less frequentty, in skeletal metastases from other human carcinomas. Our findings suggest that BMP-6 may hold potential as an attractive marker and possible mediator of skeletal metastases, particularly in prostate carcinoma.Keywords: bone morphogenetic protein-6; prostate carcinoma; skeletal metastasis; in situ hybridization: growth factors Metastases are the most common neoplastic lesions in bone. and more than 80%-7 of the tumours are accounted for by a limited number of primary malignancies (Orr et al. 1995). These include carcinomas of the breast, prostate. thyroid. kidney and lungy. Normal bone is being remodelled continuously with new bone formation by osteoblasts and bone degradation by osteoclasts. In the presence of skeletal metastases. there is a disturbance of the fine balance between the two processes. When bone destruction dominates there is net loss of bone mass and the lesion is described as osteolytic. W'hen excessise amounts of new bone formation takes place with less bone destruction. the lesion is described as osteoblastic or osteosclerotic. This type of increased ossification only occurs in relatively acellular skeletal metastases associated with the deselopment of a fibrous stroma. and is particularly common in metastases from prostatic carcinoma (Galasko. 1982). Human prostatic adenocarcinoma is one of the rare cancers that consistently produces osteoblastic metastases to bone. in approximately 90% of cases. Several growth factors which are known to stimulate osteoblast growth and bone matrix formation are also expressed in benign and malignant prostate cells. These include members of the fibroblast growth factor. insulin-lke growth factor. platelet-denried growth factor and tr...

Objective To determine the associations between the expression of waf‐1 (a cyclin‐dependent kinase inhibitor regulated by p53), p53, bcl‐2 and tumour progression in prostate cancer. Patients and methods Samples of prostatic tissue were obtained by biopsy or at prostatectomy from 40 men (mean age 73 years, range 55–88) with histologically confirmed prostate cancer, examined using immunohistochemical staining for the three gene products, and the expression related to the stage, grade, disease progression and survival of the patients. Results Fifteen of 18 patients whose tumours were positive for waf‐1, 10 of 12 positive for bcl‐2 and 17 of 19 positive for p53 had disease progression. Fifteen of 19 patients positive for p53 had poorly differentiated tumours compared with 11 of 21 negative for p53 (P<0.05). A significant number of patients positive for p53 progressed and had a shorter time to progression compared to those negative for p53 (P<0.05). There was no correlation between either waf‐1 and/or bcl‐2 staining and clinical grade, stage or tumour progression. Conclusions This study confirmed the association of p53 protein accumulation with aggressive behaviour in prostate cancer and identified waf‐1 protein in prostatic tumours. There was no evidence that the upregulation of waf‐1 was associated with a better outcome in patients with prostate cancer.

BACKGROUND The family of matrix metalloproteinases (MMPs) has been shown to be involved in proteolytic degradation of the extracellular matrix, which is an essential step in tumor invasion and metastasis. MMPs are tightly regulated by the levels of active enzymes and their inhibitors, the tissue inhibitors of metalloproteinases (TIMPs). MMP‐2 and its ratio to TIMP‐2 have been associated with tumor recurrence and progression in a number of human malignancies. METHODS We examined the relationship between MMP‐2 and TIMP‐2 mRNA expression in 42 men with malignant (n = 32) and benign (n = 10) prostates using nonisotopic in situ hybridization and Northern blot analysis. RESULTS mRNA for MMP‐2 and TIMP‐2 was localized to the malignant epithelial cells of both high‐ and low‐grade tumors in the periphery of the glands and in areas of extracapsular involvement, and to the glandular epithelium in the benign prostates. Using Northern blot analysis, the mean MMP‐2 to TIMP‐2 ratio was approximately one in the benign prostates and low‐grade and ‐stage cancers. The MMP‐2 to TIMP‐2 ratio increased to 3.3 in the high‐grade and 2.8 in the high‐stage tumors. CONCLUSIONS The results suggest a close association between MMP‐2/TIMP‐2 expression and local tumor invasion, with a disruption in expression of the two genes leading to disease progression. Future studies should focus on the activity of these enzymes and on the ratio of enzyme/inhibitor expression, which may become a useful prognostic marker in prostate cancer. Prostate 42:18–25, 2000. © 2000 Wiley‐Liss, Inc.

BACKGROUND. The family of matrix metalloproteinases (MMPs) has been shown to be involved in proteolytic degradation of the extracellular matrix, which is an essential step in tumor invasion and metastasis. MMPs are tightly regulated by the levels of active enzymes and their inhibitors, the tissue inhibitors of metalloproteinases (TIMPs). MMP-2 and its ratio to TIMP-2 have been associated with tumor recurrence and progression in a number of human malignancies. METHODS. We examined the relationship between MMP-2 and TIMP-2 mRNA expression in 42 men with malignant (n = 32) and benign (n = 10) prostates using nonisotopic in situ hybridization and Northern blot analysis. RESULTS. mRNA for MMP-2 and TIMP-2 was localized to the malignant epithelial cells of both high-and low-grade tumors in the periphery of the glands and in areas of extracapsular involvement, and to the glandular epithelium in the benign prostates. Using Northern blot analysis, the mean MMP-2 to TIMP-2 ratio was approximately one in the benign prostates and low-grade and -stage cancers. The MMP-2 to TIMP-2 ratio increased to 3.3 in the high-grade and 2.8 in the high-stage tumors. CONCLUSIONS. The results suggest a close association between MMP-2/TIMP-2 expression and local tumor invasion, with a disruption in expression of the two genes leading to disease progression. Future studies should focus on the activity of these enzymes and on the ratio of enzyme/inhibitor expression, which may become a useful prognostic marker in prostate cancer.

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