Lack of Noggin Expression by Cancer Cells Is a Determinant of the Osteoblast Response in Bone Metastases

Schwaninger, Ruth; Rentsch, Cyrill A.; Wetterwald, Antoinette; Horst, Geertje van der; Bezooijen, Rutger L. van; Pluijm, Gabri van der; Löwik, Clemens W.G.M.; Ackermann, Karin; Pyerin, Walter; Hamdy, Freddie C.; Thalmann, George N.; Cecchini, Marco

doi:10.2353/ajpath.2007.051276

Cited by 89 publications

(89 citation statements)

References 67 publications

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“…Previously, we have shown that MDA-MB-231 breast cancer cells express relatively high amounts of Noggin (Schwaninger et al, 2007). A Noggin small interfering RNA significantly further increased Smad-dependent BMP signaling under the BMP2-stimulated conditions (BMP2, þ 52%, Po0.001), but no significant effects were observed under the BMP7-and BMP2/7-stimulated conditions (BMP7, þ 18%, NS; BMP2/7, þ 14%, NS) when compared with an non-targeted small interfering RNA (Supplementary Figure 1).…”

Section: Resultsmentioning

confidence: 99%

“…By contrast, the inhibitory effect of Noggin on BMP7, and particularly BMP2/7, was less prominent. Osteolytic MDA-MB-231 breast cancer cells express relatively high amounts of Noggin (Schwaninger et al, 2007), which directly contributes to an osteolytic bone phenotype through inhibition of BMP-mediated effects on bone formation by osteoprogenitors. The observed increased potency of BMP2/7 (compared with BMP2 or BMP7 alone) may, therefore, at least in part be caused by the increase in bioavailability due to the diminished efficacy of locally produced Noggin.…”

Section: Bmp2/7 Inhibits the Breast Cancer Stem Cell Subpopulation Jtmentioning

confidence: 99%

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The BMP2/7 heterodimer inhibits the human breast cancer stem cell subpopulation and bone metastases formation

et al. 2011

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Accumulating evidence suggests that a subpopulation of breast cancer cells, referred to as cancer stem cells (CSCs), have the ability to propagate a tumor and potentially seed new metastases. Furthermore, stimulation of an epithelialto-mesenchymal transition by factors like transforming growth factor-b (TGFb) is accompanied with the generation of breast CSCs. Previous observations indicated that bone morphogenetic protein-7 (BMP7) antagonizes the protumorigenic and prometastatic actions of TGFb, but whether BMP7 action is mechanistically linked to breast CSCs has remained elusive. Here, we have studied the effects of BMP7, BMP2 and a BMP2/7 heterodimer on the formation of human breast CSCs (ALDH hi /CD44 hi / CD24 À/low ) and bone metastases formation in a preclinical model of intra-cardiac injection of MDA-MB-231 cells in athymic nude (Balb/c nu/nu) mice. The BMP2/7 heterodimer was the most efficient stimulator of BMP signaling and very effectively reduced TGFb-driven Smad signaling and cancer cell invasiveness. The tested BMPs-particularly the heterodimeric BMP2/7-strongly reduced the size of the ALDH hi /CD44 hi /CD24 À/low CSC subpopulation. In keeping with these in vitro observations, pretreatment of cancer cells with BMPs for 72 h prior to systemic inoculation of the cancer cells inhibited the formation of bone metastases. Collectively, our data support the notion that breast CSCs are involved in bone metastasis formation and describe heterodimeric BMP2/7 as a powerful TGFb antagonist with anti-metastatic potency.

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Section: Resultsmentioning

confidence: 99%

Section: Bmp2/7 Inhibits the Breast Cancer Stem Cell Subpopulation Jtmentioning

confidence: 99%

The BMP2/7 heterodimer inhibits the human breast cancer stem cell subpopulation and bone metastases formation

et al. 2011

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“…This indicates that functional TGF␤ and BMP receptors are present in these cells, thus confirming our earlier observations. 22,24 Exogenous addition of BMP7 but not of TGF␤ strongly stimulated BRE 4 -luciferase activity in PC-3M-Pro4 cells and indicated the presence of functioning, activated type 1 BMP-receptor complexes in these prostate cancer cells (Figure 5b). Strikingly, when BMP7 and TGF␤ were given simultaneously, BRE 4 -luciferase activity was significantly stimulated in a synergistic manner (Figure 5b).…”

Section: Bmp7 and Epithelial-to-mesenchymal Transition In Prostate Camentioning

confidence: 99%

“…BMP7 mRNA levels in prostate cancer cell lines strongly correlated to E-cadherin/vimentin ratio (Figure 2, a and b), whereas no association was observed for other BMPs (results not shown). 24 The highly tumorigenic and metastatic human prostate cancer cell line PC-3 and its derivative PC-3M-Pro4 did not show detectable BMP7 mRNA expression (Figure 2b) and protein synthesis in vitro (human specific BMP7 enzyme-linked immunosorbent assay; all Ͻ10 pg/ml hBMP7, n ϭ 4). The lack of BMP7 expression by PC-3M-Pro4 cells in vitro was confirmed in vivo in bone metastases (Figure 2d), suggesting that the bone microenvironment is unable to induce BMP7 expression in metastatic cancer cells.…”

Section: Bmp7 Mrna Expression In Prostate Cancer Cell Linesmentioning

confidence: 99%

BMP7, a Putative Regulator of Epithelial Homeostasis in the Human Prostate, Is a Potent Inhibitor of Prostate Cancer Bone Metastasis in Vivo

Buijs

Rentsch

Horst

et al. 2007

The American Journal of Pathology

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185

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Bone morphogenic protein 7 (BMP7) counteracts physiological epithelial-to-mesenchymal transition, a process that is indicative of epithelial plasticity. Because epithelial-to-mesenchymal transition is involved in cancer, we investigated whether BMP7 plays a role in prostate cancer growth and metastasis. BMP7 expression in laser-microdissected primary human prostate cancer tissue was strongly down-regulated compared with normal prostate luminal epithelium. Furthermore, BMP7 expression in prostate cancer cell lines was inversely related to tumorigenic and metastatic potential in vivo and significantly correlated to E-cadherin/vimentin ratios. Exogenous addition of BMP7 to human prostate cancer cells dose-dependently inhibited transforming growth factor ␤-induced activation of nuclear Smad3/4 complexes via ALK5 and induced E-cadherin expression. Moreover, BMP7-induced activation of nuclear Smad1/4/5 signaling transduced via BMP type I receptors was synergistically stimulated in the presence of transforming growth factor ␤, a growth factor that is enriched in the bone microenvironment. Daily BMP7 administration to nude mice inhibited the growth of cancer cells in bone. In contrast, no significant growth inhibitory effect of BMP7 was observed in intraprostatic xenografts. Collectively, our observations suggest that BMP7 controls and preserves the epithelial phenotype

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“…Conversely, the induction of Dkk-1 in the mixed osteoblastic/osteolytic prostate cancer C4-2B cell line results in experimental bone metastases with an osteolytic phenotype in vivo. Dickkopf-1 expression in human breast cancer cell lines has been recently reported at mRNA level (Schwaninger et al, 2007).…”

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confidence: 99%

Increased Dickkopf-1 expression in breast cancer bone metastases

Voorzanger-Rousselot¹,

et al. 2007

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The aim of this study was to determine whether Dickkopf-1 (Dkk-1) expression in breast cancer was associated with bone metastases. We first analysed Dkk-1 expression by human breast cancer cell lines that induce osteolytic or osteoblastic lesions in animals. Dickkopf-1 levels were then measured in the bone marrow aspirates of hind limbs from eight NMRI mice inoculated with breast cancer cells that induced bone metastases and 11 age-matched non-inoculated control animals. Finally, Dkk-1 was measured in the serum of 17 women with breast cancer in complete remission, 19 women with breast cancer and bone metastases, 16 women with breast cancer and metastases at non-bone sites and 16 healthy women. Only breast cancer cells that induce osteolytic lesions in animals produced Dkk-1. There was a six-fold increase in Dkk-1 levels in the bone marrow from animals inoculated with MDA-B02 cells when compared with that of control non-inoculated animals (P ¼ 0.003). Median Dkk-1 levels in the serum of patients with breast cancer and bone metastases were significantly higher than levels of patients in complete remission (P ¼ 0.016), patients with breast cancer having metastases at non-bone sites (Po0.0001) and healthy women (P ¼ 0.047), although there was a large overlap in individual levels between the different groups. In conclusion, Dkk-1 is secreted by osteolytic human breast cancer cells lines and increased circulating levels are associated with the presence of bone metastases in patients with breast cancer. Measurements of circulating Dkk-1 levels may be useful for the clinical investigation of patients with breast cancer and bone metastases.

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Lack of Noggin Expression by Cancer Cells Is a Determinant of the Osteoblast Response in Bone Metastases

Cited by 89 publications

References 67 publications

The BMP2/7 heterodimer inhibits the human breast cancer stem cell subpopulation and bone metastases formation

The BMP2/7 heterodimer inhibits the human breast cancer stem cell subpopulation and bone metastases formation

BMP7, a Putative Regulator of Epithelial Homeostasis in the Human Prostate, Is a Potent Inhibitor of Prostate Cancer Bone Metastasis in Vivo

Increased Dickkopf-1 expression in breast cancer bone metastases

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