Bone morphogenetic protein 6 in skeletal metastases from prostate cancer and other common human malignancies

Abstract

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...

Bone morphogenetic protein-6: potential mediator of osteoblastic metastases in prostate cancer

“…9 Primary tumours included prostate (n 13), lung (n 8), kidney (n 2), breast (n 5), colon (n 1) and uterus (n 1). In addition primary tumour was obtained for three of the patients with prostate secondaries from transurethral resection specimens.…”

The role of inhibins and activins in prostate cancer pathogenesis.

“…PDF expression in the prostate is regulated by androgens (Paralkar et al 1998). BMP-2 and BMP-6 were both identified in prostate cancers (Ide et al 1997, Autzen et al 1998, Thomas et al 1998a. Interest in the role they might play in the pathogenesis of bony metastases in prostate cancer is under investigation.…”

The prognostic significance of BMP-6 signaling in prostate cancer

“…Because BMP-6 activity has been suggested to correlate with the ability of the prostate cancer to establish bone metastasis, 6,7,12 we therefore analyzed our patient cohort, excluding those metastatic patients with their secondary lesion developed other than in bone, on whether increased BMP-6 activity could predict development of metastasis to bone. We found that, by Kaplan-Meier analysis, patients with primary prostate cancer expressing high level of BMP-6 and low level of noggin had a higher chance for the development of bone metastasis (Figure 4f, P ¼ 0.032), whereas patients with primary prostate cancer expressing high level of BMP-6 and low level of both noggin and sclerostin also had a higher chance for the development of bone metastasis (Figure 4g, P ¼ 0.028).…”