Biomedical subjects

Martine Deckers

Publications and source records attributed to Martine Deckers.

5 recordsLinked to original sources

PubMed2006

The tumor suppressor Smad4 is required for transforming growth factor beta-induced epithelial to mesenchymal transition and bone metastasis of breast cancer cells.

Transforming growth factor beta (TGF-beta) can act as suppressor and promoter of cancer progression. Intracellular Smad proteins (i.e., receptor regulated Smads and common mediator Smad4) play a pivotal role in mediating antimitogenic and proapoptotic effects of TGF-beta, but their function in TGF-beta-induced invasion and metastasis is unclear. Here, we have investigated the role of Smad4 in a cellular and mouse model for TGF-beta-induced breast cancer progression. Consistent with its tumor suppressor function, specific silencing of Smad4 in NMuMG mammary gland epithelial cells using small hairpin RNA (shRNA)-expressing RNAi vectors strongly mitigated TGF-beta-induced growth inhibition and apoptosis. Smad4 knockdown also potently inhibited TGF-beta-induced epithelial to mesenchymal transition of NMuMG cells as measured by morphologic transformation from epithelial to fibroblast-like cells, formation of stress fibers, inhibition of E-cadherin expression, and gain of expression of various mesenchymal markers. Furthermore, we show that knockdown of Smad4 in MDA-MB-231 breast cancer cells strongly inhibited the frequency of bone metastasis in nude mice by 75% and significantly increased metastasis-free survival. Communication of MDA-MB-231 cells with the bone microenvironment, which is needed for optimal tumor cell growth and metastasis, may be affected in Smad4 knockdown cells as TGF-beta-induced expression of interleukin 11 was attenuated on Smad4 knockdown. Taken together, our results show that Smad4 plays an important role in both tumor suppression and progression of breast cancer cells.

Animals↗

PubMed2005

TGF-beta receptor function in the endothelium.

Genetic studies in mice and humans have revealed the pivotal role of transforming growth factor-beta (TGF-beta) signaling during angiogenesis. Mice deficient for various TGF-beta signaling components present an embryonic lethality due to vascular defects. In patients, mutations in the TGF-beta type I receptor ALK1 or in the accessory TGF-beta receptor endoglin are linked to an autosomal dominant disorder of vascular dysplasia termed Hereditary Haemorrhagic Telangiectasia (HHT). It has puzzled researchers for years to explain the effects of TGF-beta being a stimulator and an inhibitor of angiogenesis in vitro and in vivo. Recently, a model has been proposed in which TGF-beta by binding to the TGF-beta type II receptor can activate two distinct type I receptors in endothelial cells (ECs), i.e., the EC-restricted ALK1 and the broadly expressed ALK-5, which have opposite effects on ECs behavior. ALK1 via Smad1/5 transcription factors stimulates EC proliferation and migration, whereas ALK5 via Smad2/3 inhibits EC proliferation and migration. Here, the new findings are presented concerning the molecular mechanisms that take place in ECs to precisely regulate and even switch between TGF-beta-induced biological responses. In particular, the role of the accessory TGF-beta receptor endoglin in the regulation of EC behavior is addressed and new insights are discussed concerning the possible mechanisms that are implicated in the development of HHT.

Animals↗

PubMed2005

Transforming growth factor-beta signal transduction in angiogenesis and vascular disorders.

Transforming growth factor (TGF)-beta is a multifunctional protein that initiates its diverse cellular responses by binding to and activating specific type I and type II serine/threonine kinase receptors. TGF-beta can act as a regulator of proliferation, migration, survival, differentiation, and extracellular matrix synthesis in endothelial cells and vascular smooth muscle cells, as well as in the maintenance of vascular homeostasis. Importantly, genetic studies in humans have revealed the pivotal role of TGF-beta as well as its signaling components in angiogenesis. Mutations in two TGF-beta receptors (ie, the activin receptor-like kinase (ALK) 1 and the accessory TGF-beta receptor endoglin) have been linked to vascular disorders named hereditary hemorrhagic telangiectasia. In addition, knockout mice for the different components of the TGF-beta signaling pathway have shown that TGF-beta is indispensable for angiogenesis. Recent studies have revealed that TGF-beta can regulate vascular homeostasis by balancing the signaling between two distinct TGF-beta type I receptors (ie, the endothelial-restricted ALK1 and the broadly expressed ALK5 receptors). The activation of these receptors has been shown to induce opposite effects on endothelial cell behavior and angiogenesis. In this review, we will present recent advances in understanding the role of TGF-beta signaling in endothelial cells as well as the underlying molecular mechanisms by which perturbation of this pathway can lead to vascular disorders.

Animals↗

PubMed2003

In vitro and in vivo endochondral bone formation models allow identification of anti-angiogenic compounds.

A major obstacle in the study of angiogenesis and the testing of new agents with anti-angiogenic potential has been the lack of experimental models with predictive in vivo value. We describe here the combined use of in vitro and in vivo angiogenesis models that are based on endochondral bone development. This approach led to the identification of a new inhibitor of matrix metalloprotease (MMP) activity that inhibits neovascularization in vitro and in vivo while osteoclast invasion, which occurs simultaneously during bone development, remained unaffected. In contrast, the broad-spectrum MMP-inhibitor marimastat inhibited both in vitro angiogenesis and osteoclastogenesis dose-dependently but displayed severe toxic side effects in vivo. The combined use of these experimental models may, therefore, facilitate the discovery of mechanisms underlying angiogenesis and lead to identification of new pharmacological compounds with clinical efficacy and appropriate selectivity in the treatment of angiogenesis-dependent disorders like arthritis and cancer.

Angiogenesis Inhibitors↗

PubMed2002

Design of a variant of vascular endothelial growth factor-A (VEGF-A) antagonizing KDR/Flk-1 and Flt-1.

Because of its central role in pathological angiogenesis, vascular endothelial growth factor (VEGF) has become a major target for anti-angiogenic therapies. We report here the construction of a heterodimeric antagonistic VEGF variant (HD-VEGF). In this antagonist, binding domains for the VEGF-receptors KDR/Flk-1 and Flt-1 are present at one pole of the dimer, whereas the other pole carries domain swap mutations, which prevent binding to either receptor. As HD-VEGF can only bind to monomeric receptors, it does not lead to signal transduction. Moreover, it antagonizes VEGF and possibly other members of the VEGF family, which are KDR/Flk-1 and Flt-1 ligands. We show here that HD-VEGF is a potent inhibitor of VEGF-mediated proliferation and tissue factor induction in endothelial cell cultures, requiring only a 20-fold and a 4-fold excess, respectively, to block the activity of wtVEGF completely. A 4-fold excess of HD-VEGF over wtVEGF was also sufficient to abrogate vascular permeability as determined in the Miles assay in vivo. Furthermore, HD-VEGF inhibited fetal bone angiogenesis in an ex vivo assay. Thus, HD-VEGF blocks KDR- and Flt-1-mediated VEGF activities that are crucial in the angiogenic process and is therefore a promising, multipotent compound in the treatment of angiogenesis-related diseases.

Amino Acid Sequence↗