Bone Morphogenetic Protein-4 Inhibits Corticotroph Tumor Cells: Involvement in the Retinoic Acid Inhibitory Action

Giacomini, Damiana; Páez-Pereda, Marcelo; Theodoropoulou, Marily; Labeur, Marta; Refojo, Damián; Gerez, Juan; Chervin, Alberto; Berner, S.; Losa, Marco; Buchfelder, Michael; Renner, Ulrich; Stalla, Günter; Arzt, Eduardo

doi:10.1210/en.2005-0958

Cited by 78 publications

(87 citation statements)

References 52 publications

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“…Expression of several other regulators of BMP-4 signaling is also induced by BMP-4, raising the possibility that blockade of relevant signaling inhibitors might enhance the efficacy of BMP-4 treatment. Previous in vivo studies have described antitumorigenic effects of BMP-4 for (40,(45)(46)(47)-as well as protumorigenic effects for some-but thus far only one other study, using a model of glioblastoma multiforme, has demonstrated an antitumor effect of therapeutically administered recombinant BMP-4 (48). Although the authors identified a prodifferentiation effect on tumor stem cells, we noted that VEGF-D is highly expressed in glioblastoma multiforme (49).…”

Section: Discussionmentioning

confidence: 59%

A Role for Bone Morphogenetic Protein-4 in Lymph Node Vascular Remodeling and Primary Tumor Growth

et al. 2011

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Lymph node metastasis, an early and prognostically important event in the progression of many human cancers, is associated with expression of VEGF-D. Changes to lymph node vasculature that occur during malignant progression may create a metastatic niche capable of attracting and supporting tumor cells. In this study, we sought to characterize molecules expressed in lymph node endothelium that could represent therapeutic or prognostic targets. Differential mRNA expression profiling of endothelial cells from lymph nodes that drained metastatic or nonmetastatic primary tumors revealed genes associated with tumor progression, in particular bone morphogenetic protein-4 (BMP-4). Metastasis driven by VEGF-D was associated with reduced BMP-4 expression in high endothelial venules, where BMP-4 loss could remodel the typical high-walled phenotype to thin-walled vessels. VEGF-D expression was sufficient to suppress proliferation of the more typical BMP-4-expressing high endothelial venules in favor of remodeled vessels, and mechanistic studies indicated that VEGF receptor-2 contributed to high endothelial venule proliferation and remodeling. BMP-4 could regulate high endothelial venule phenotype and cellular function, thereby determining morphology and proliferation responses. Notably, therapeutic administration of BMP-4 suppressed primary tumor growth, acting both at the level of tumor cells and tumor stromal cells. Together, our results show that VEGF-D-driven metastasis induces vascular remodeling in lymph nodes. Furthermore, they implicate BMP-4 as a negative regulator of this process, suggesting its potential utility as a prognostic marker or antitumor agent. Cancer Res; 71(20); 6547-57. Ó2011 AACR.

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Section: Discussionmentioning

confidence: 59%

A Role for Bone Morphogenetic Protein-4 in Lymph Node Vascular Remodeling and Primary Tumor Growth

et al. 2011

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“…A binding protein for BMPs, noggin expression is conversely downregulated in the prolactinoma from the D2R-null mouse (Paez-Pereda et al 2003), suggesting that BMP-4 promotes cell proliferation in lactotropes in conjunction with Smad-estrogen receptor interaction under the influence of its binding protein. BMP-4 also inhibits adrenocorticotropin secretion and cell proliferation of corticotropinoma cells (Giacomini et al 2006). This BMP-4 action seems to be involved in the anti-proliferative effect induced by retinoic acid on corticotropinomas.…”

Section: Discussionmentioning

confidence: 91%

“…This BMP-4 action seems to be involved in the anti-proliferative effect induced by retinoic acid on corticotropinomas. Thus, BMP-4 promotes pituitary prolactinoma through Smad-estrogen receptor crosstalk (Paez-Pereda et al 2003) while BMP-4 inhibits corticotrope pathogenesis of Cushing's disease (Giacomini et al 2006).…”

Section: Discussionmentioning

confidence: 99%

“…For instance, BMP-4 promotes pituitary prolactinoma pathogenesis through crosstalk between the BMP-4-mediated Smads and the estrogen receptor (Paez-Pereda et al 2003). BMP-4 also inhibits corticotropic pathogenesis and Cushing's disease in adult pituitary tumor cells (Giacomini et al 2006). Thus, the pituitary BMP system likely acts as a regulator not only for organogenesis and differentiation process of pituitary cells, but also for transformation and tumorigenesis of the differentiated pituitary cells.…”

Section: Introductionmentioning

confidence: 99%

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Involvement of bone morphogenetic protein-4 in GH regulation by octreotide and bromocriptine in rat pituitary GH3 cells

Miyoshi¹,

Otsuka²,

Otani³

et al. 2008

Journal of Endocrinology

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Here we investigated roles of the pituitary bone morphogenetic protein (BMP) system in modulating GH production regulated by a somatostatin analog, octreotide (OCT) and a dopamine agonist, bromocriptine (BRC) in rat pituitary somatolactotrope tumor GH3 cells. The GH3 cells were found to express BMP ligands, including BMP-4 and BMP-6; BMP type-1 and type-2 receptors (except the type-1 receptor, activin receptor-like kinase (ALK)-6); and Smad signaling molecules. Forskolin stimulated GH production in accordance with cAMP synthesis. BRC, but not OCT, suppressed forskolin-induced cAMP synthesis by GH3 cells. Individual treatment with OCT and BRC reduced forskolininduced GH secretion. A low concentration (0 . 1 mM) of OCT in combination with BRC (1-100 mM) exhibited additive effects on reducing GH and cAMP production induced by forskolin. However, a high concentration (10 mM) of OCT in combination with BRC failed to suppress GH and cAMP production. BMP-4 specifically enhanced GH secretion and cAMP production induced by forskolin in GH3 cells. BRC, but not OCT, inhibited BMP-4-induced activation of Smad1,5,8 phosphorylation and Id-1 transcription and decreased ALK-3 expression. Of note, in the presence of a high concentration of OCT, the BRC effects suppressing BMP-4-Smad1,5,8 signaling were significantly impaired. In the presence of BMP-4, a high concentration of OCT also attenuated the BRC effects suppressing forskolin-induced GH and cAMP production. Collectively, a high concentration of OCT interferes with BRC effects by reducing cAMP production and suppressing BMP-4 signaling in GH3 cells. These findings may explain the mechanism of resistance of GH reduction to a combination therapy with OCT and BRC for GH-producing pituitary adenomas.

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“…Retinoic acid induces both BMP-4 transcription and expression and its antiproliferative action is blocked in Smad-4 dominant negative and noggin transfected Att-20 cells that do not respond to BMP-4. Therefore, BMP-4 is induced by and mediates some of the retinoic acid effects [62].…”

Section: Bmp-4 Involvement In the Retinoic Acid Inhibitory Actionmentioning

confidence: 99%

Potential of retinoic acid derivatives for the treatment of corticotroph pituitary adenomas

Labeur

Paez-Pereda²,

Arzt

et al. 2008

Rev Endocr Metab Disord

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Cushing's disease is a severe clinical condition caused by hypersecretion of corticosteroids due to excessive ACTH secretion from a pituitary adenoma. This complex endocrine disorder still represents a major challenge for the physician in terms of efficient treatment. In the last years there was only little progress in elucidating the molecular mechanisms responsible for the constitutive and autonomous ACTH secretion of pituitary corticotrophinomas. As a consequence, no effective drug therapy is currently available, particularly if surgical excision is not successful. In the present article we examine recent studies that have investigated the therapeutic potential of retinoic acid receptors as nuclear receptor targets for the treatment of Cushing's disease. Retinoic acid is an efficient drug used for the treatment of different types of cancers and it proved to act in animal models of Cushing's disease. The efficiency of this treatment in patients with this disorder still needs to be tested in clinical trials.

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Bone Morphogenetic Protein-4 Inhibits Corticotroph Tumor Cells: Involvement in the Retinoic Acid Inhibitory Action

Cited by 78 publications

References 52 publications

A Role for Bone Morphogenetic Protein-4 in Lymph Node Vascular Remodeling and Primary Tumor Growth

A Role for Bone Morphogenetic Protein-4 in Lymph Node Vascular Remodeling and Primary Tumor Growth

Involvement of bone morphogenetic protein-4 in GH regulation by octreotide and bromocriptine in rat pituitary GH3 cells

Potential of retinoic acid derivatives for the treatment of corticotroph pituitary adenomas

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