Bone morphogenetic protein-6 expression in normal and malignant prostate

Barnes, Jean; Anthony, Catherine T.; Wall, Nancy A.; Steiner, Mitchell S.

doi:10.1007/bf00191214

Cited by 59 publications

(45 citation statements)

References 20 publications

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“…This result was in line with other findings, suggesting that BMP-6 might play a role in prostate cancer progression. 4 In contrast, we did not observe significant different noggin or sclerostin staining between high-and low-grade prostate cancers in our patient cohort. These results suggest that loss of BMPs inhibitors might not be a feature of high-grade prostate cancer.…”

Section: Bmp-6 Expression Is Upregulated In High-grade Prostate Cancercontrasting

confidence: 82%

“…BMP-6 expression is higher in prostate cancer compared with benign prostate specimens as well as in high-grade compared with low-grade prostate cancers. 4,5 Its expression is high in primary prostate cancer of patients with metastases, whereas is low or undetectable in nonmetastatic prostate cancer and benign prostate specimens. 1,5 In addition, BMP-6 is also highly expressed in prostate cancer metastasized to bone.…”

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confidence: 99%

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The prognostic significance of BMP-6 signaling in prostate cancer

et al. 2008

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The importance of bone-morphogenetic proteins in prostate cancer is well recognized. Bone-morphogenetic protein-6 overexpression has been shown to increase the aggressiveness and invasiveness of prostate cancer cells. Recent studies on noggin and sclerostin, potent inhibitors of bone-morphogenetic protein signaling, have found that noggin also modifies the ability of prostate cancer cells to metastasize to bone. Taken together, these results suggest that bone-morphogenetic protein-6 signaling is important in prostate cancer progression. Our study investigated the expression of bone-morphogenetic protein-6, noggin and sclerostin in human prostate specimens (n ¼ 136) by immunohistochemical staining. We found that bone-morphogenetic protein-6 was increased (Po0.001), whereas sclerostin was decreased (P ¼ 0.004) in prostate cancer compared with nodular hyperplasia. In addition, significantly higher level of bone-morphogenetic protein-6 expression was observed in high-grade prostate cancer with Gleason score Z7 (P ¼ 0.027). Bone-morphogenetic protein-6, noggin and sclerostin alone could not predict the development of distant metastasis in our patient cohort. However, high level of bone-morphogenetic protein-6 and low level of noggin, or high level of bonemorphogenetic protein-6 and low level of both noggin and sclerostin expression in primary prostate cancer significantly predicted development of distant metastasis. The predictive value was still valid when only high-grade prostate cancers were included or when patients with secondary lesion other than bone were excluded. Taken together, these results suggest that a high level of bone-morphogenetic protein-6 signaling, resulting from increased expression of bone-morphogenetic protein-6 and decreased expression of its inhibitors, might promote the development of prostate cancer metastases. Our results also imply the potential use of bone-morphogenetic protein-6, noggin and sclerostin expression together as a prognostic predictor for metastatic progression of prostate cancer.

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Section: Bmp-6 Expression Is Upregulated In High-grade Prostate Cancercontrasting

confidence: 82%

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confidence: 99%

The prognostic significance of BMP-6 signaling in prostate cancer

et al. 2008

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“…BMP-6 expression was detected in the prostate tissue of over 50% of patients with clinically defined metastatic prostate cancer, but was not detected in nonmetastatic or benign prostate samples. In another study focused on BMP-6 mRNA and protein expression, Barnes et al (24) observed that BMP-6 was produced by normal and neoplastic human prostate (radical prostatectomy specimens and human carcinoma cell lines DU145 and PC3). However, BMP-6 mRNA and protein expression was higher in prostate cancer compared with adjacent normal prostate, with higher-grade tumors (Gleason score of 6 or more) having greater BMP-6 immunostaining than the lower-grade tumors (Gleason score of 4 or less).…”

Section: Discussionmentioning

confidence: 99%

“…Although the expressions of several BMPs have been evaluated in prostate cancer, BMP-6 seems to be most consistently increased with increasing progression of prostate cancer (24,25). This observation, taken together with the knowledge that BMPs are pro-osteoblastic and induce bone formation, led us to hypothesize that up-regulation of BMP-6 expression in prostate cancer cells localized in the bone contributes to the development of osteoblastic lesions at prostate cancer metastatic sites in bone.…”

Section: Introductionmentioning

confidence: 99%

Bone Morphogenetic Protein-6 Promotes Osteoblastic Prostate Cancer Bone Metastases through a Dual Mechanism

et al. 2005

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Prostate cancer frequently metastasizes to bone where it forms osteoblastic lesions through unknown mechanisms. Bone morphogenetic proteins (BMP) are mediators of skeletal formation. Prostate cancer produces a variety of BMPs, including BMP-6. We tested the hypothesis that BMP-6 contributes to prostate cancer-induced osteosclerosis at bone metastatic sites. Prostate cancer cells and clinical tissues produced BMP-6 that increased with aggressiveness of the tumor. Prostate cancer-conditioned medium induced SMAD phosphorylation in the preosteoblast MC3T3 cells, and phosphorylation was diminished by anti-BMP-6 antibody. Prostate cancer-conditioned medium induced mineralization of MC3T3 cells, which was blocked by both the BMP inhibitor noggin and anti-BMP-6. Human fetal bones were implanted in severe combined immunodeficient mice and after 4 weeks, LuCaP 23.1 prostate cancer cells were injected both s.c. and into the bone implants. Anti-BMP-6 or isotype antibody administration was then initiated. Anti-BMP-6 reduced LuCaP 23.1-induced osteoblastic activity, but had no effect on its osteolytic activity. This was associated with increased osteoblast numbers and osteoblast activity based on bone histomorphometric evaluation. As endothelin-1 has been implicated in bone metastases, we measured serum endothelin-1 levels but found they were not different among the treatment groups. In addition to decreased bone production, anti-BMP-6 reduced intraosseous, but not s.c., tumor size. We found that BMP-2, BMP-4, BMP-6, and BMP-7 had no direct effect on prostate cancer cell growth, but BMP-2 and BMP-6 increased the in vitro invasive ability of prostate cancer cell. These data show that prostate cancer promotes osteoblastic activity through BMP-6 and that, in addition to its bone effects, suggest that BMPs promote the ability of the prostate cancer cells to invade the bone microenvironment. (Cancer Res 2005; 65(18): 8274-85)

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“…Putative factors secreted by prostate cancer cells that affect osteoblast growth and differentiation could be involved in the progression of prostate cancer in bone (8). Several candidate factors including endothelin-1 (9), platelet-derived growth factor (10), and BMP-6 (11,12) have been identified. We previously identified a 45-kDa secreted isoform of ErbB-3 (p45-sErbB3, previously named MDA-BF-1) from the supernatants of bone marrow samples from men with prostate cancer and bone metastasis (13).…”

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Soluble ErbB3 Levels in Bone Marrow and Plasma of Men with Prostate Cancer

Lin

Lee

Choueiri

et al. 2008

Clinical Cancer Research

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Purpose: Prostate cancer tends to metastasize to bone and induce osteoblastic lesions. We identified a soluble form of ErbB3 (sErbB3), p45-sErbB3, in bone marrow supernatant from men with prostate cancer bone metastasis and showed that p45-sErbB3 enhances bone formation. We aimed to understand clinical implications of sErbB3 by establishing an ELISA to detect sErbB3 levels in bone marrow and plasma samples. Experimental Design: We did ELISAs on marrow from 108 men [34 with androgen-dependent disease, 30 with androgen-independent disease (AI) but negative bone scan (AI/BS-), and 44 with AI and positive bone scan (AI/BS+)], sequential marrow from 5 men during treatment, plasma from 52 men before and after docetaxel treatment, and plasma from 95 men ages z70 years old without prostate cancer. Results: Some men with clinically detectable bone metastasis had high sErbB3 levels.Within the AI/BS-group, higher sErbB3 levels seemed to yield lower rates of bone metastasis. In the AI/BS+ group, detectable bone metastases took longer to appear in men with higher sErbB3 levels than in men with lower sErbB3 levels (median, 82 versus 41 months). However, high sErbB3 levels did not confer survival benefit after metastasis development. Among men with metastatic progression in bone, docetaxel treatment reduced plasma sErbB3 (P < 0.0001) but did not affect bone-specific alkaline phosphatase (P = 0.206) or prostate-specific antigen (P = 0.906). sErbB3 was also detected in men without prostate cancer. Conclusions: The apparent correlation between higher sErbB3 levels and longer time to bone metastasis suggests that sErbB3 participates in progression in bone of prostate cancer.Advanced prostate cancer often metastasizes to distant sites, most commonly bone (1). Bone metastases from prostate cancer are primarily osteoblastic, with an overall increase in bone formation (1). In contrast, bone metastases from lung, kidney, or breast are frequently osteolytic (2). The effect of osteoblastic reaction on the progression of prostate cancer in bone is not clear. Interestingly, metastases of prostate cancer seem to progress more slowly than do osteolytic metastases associated with other tumors. Nevertheless, development of bone metastases confers poor prognosis (3), and no effective strategy has been found to prolong survival among men with metastatic prostate cancer at this stage.Despite similarities in clinical presentation, a recent study of the pathologic, immunologic, and molecular features of specimens of prostate cancer bone metastases at autopsy showed that metastatic hormone-refractory prostate cancer is actually a heterogeneous group of diseases (4). Findings from that study further suggested that different foci of metastatic disease within the same individual could vary in immunophenotype and genotype (4). These observations underscore the difficulty in identifying biomarkers for the early detection of bone metastasis and in designing strategies to treat or prevent the progression of disease. Understanding the mechanisms of...

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Bone morphogenetic protein-6 expression in normal and malignant prostate

Cited by 59 publications

References 20 publications

The prognostic significance of BMP-6 signaling in prostate cancer

The prognostic significance of BMP-6 signaling in prostate cancer

Bone Morphogenetic Protein-6 Promotes Osteoblastic Prostate Cancer Bone Metastases through a Dual Mechanism

Soluble ErbB3 Levels in Bone Marrow and Plasma of Men with Prostate Cancer

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