Plexin-B1 plays a redundant role during mouse development and in tumour angiogenesis

Fazzari, Pietro; Penachioni, Junia Y.; Gianola, Sara; Rossi, Ferdinando; Eickholt, Britta J.; Maina, Flavio; Alexopoulou, Lena; Sottile, Antonino; Comoglio, Paolo M.; Flavell, Richard A.; Tamagnone, Luca

doi:10.1186/1471-213x-7-55

Cited by 72 publications

(62 citation statements)

References 42 publications

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“…When Sema4D levels were reduced with shRNA-expressing lentiviruses, this pro-angiogenic phenotype was greatly attenuated, though it should be noted not totally blocked. This could be due to functional redundancy for Sema4D/Plexin-B1-mediated angiogenesis, which has been observed in a knock-out study (23), and the fact that HIF-1␣-overexpressing cells still produce other proteins that are components of the hypoxia response and could promote angiogenesis, such as VEGF.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia-inducible Factor-1-mediated Regulation of Semaphorin 4D Affects Tumor Growth and Vascularity

Sun

Zhou

Binmadi

et al. 2009

Journal of Biological Chemistry

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Tumor progression and metastasis depend on the ability of cancer cells to initiate angiogenesis to ensure delivery of oxygen, nutrients, and growth factors to tumor cells and provide access to the systemic circulation. Hypoxia-inducible factor-1 (HIF-1) can activate expression of a broad range of genes that mediate many of the adaptive responses to decreased oxygen concentration, such as enhanced glucose uptake and formation of new blood vessels. Acting through Plexin-B1 on endothelial cells, Semaphorin 4D (Sema4D) has been shown to promote angiogenesis and enhance invasive growth and proliferation in some tumors. Here we show that the gene for Sema4D, the product of which is elevated in head and neck squamous cell carcinoma (HNSCC) cells, contains upstream hypoxia response elements (HRE) and is strongly induced in hypoxia in a HIF-1-dependent manner. Knocking down Sema4D expression with short hairpin (sh) RNA reduces in vitro endothelial cell migration and growth and vascularity of HNSCC xenografts expressing a degradation resistant HIF-1␣ subunit. We also demonstrate a correlation between HIF-1 activity and Sema4D expression in HNSCC specimens. These findings indicate that Sema4D is induced by hypoxia in a HIF-1-dependent manner and influences endothelial cell migration and tumor vascularity. Expression of Sema4D may be a strategy by which carcinomas promote angiogenesis and therefore could represent a therapeutic target for these malignancies.The semaphorins and plexins comprise a family of proteins shown to control proliferation and survival in many different cells and tissues, including the nervous system, the immune system (1), and the vasculature (2). Such diversity of function likely arises as a result of homology with the scatter factor family of proteins, which are known to participate in branching morphogenesis and normal and aberrant motility in numerous cell types (3). Currently, more than 20 semaphorins have been identified that are grouped into eight classes (4). Plexins, which are receptors for the semaphorins, share homology in their extracellular segment with the scatter factor receptors c-Met and RON. In humans, at least nine plexins have been identified and grouped into four families, A through D, most of which have been shown to mediate neuronal cell adhesion and axon guidance (5). We have demonstrated that Semaphorin 4D (Sema4D) 2 is overexpressed by many different aggressive carcinomas, including head and neck squamous cell carcinoma (HNSCC), and that its activity on endothelial cells, which express its receptor Plexin-B1, promotes enhanced growth and vascularity of tumor xenografts in vivo (6). Why Sema4D is overexpressed in so many different tumor types remains unknown, but like other pro-angiogenic factors, plexins and semaphorins may be regulated by changes in oxygen tension (7).The hypoxia-inducible factor-1 (HIF-1) transcriptional complex is the 'master control switch' for hypoxia. Initially identified by Semenza and colleagues in the early 1990s, HIF-1 is composed of two polypeptide...

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Section: Discussionmentioning

confidence: 99%

Hypoxia-inducible Factor-1-mediated Regulation of Semaphorin 4D Affects Tumor Growth and Vascularity

Sun

Zhou

Binmadi

et al. 2009

Journal of Biological Chemistry

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“…1E). To confirm our results further, particularly in the light of a recent contradictory publication (Fazzari et al, 2007) that has reported plexin B1 expression in the mesenchyme, we took advantage of a mouse line expressing the reporter gene product β-galactosidase under the control of the plexin B1 promoter (Plxnb1lacZ). This knock-in reporter reflects closely the developmental expression pattern of plexin B1 in the nervous system, because the entire promoter elements of the Plxnb1 gene are available to direct lacZ expression (Friedel et al, 2007).…”

Section: Research Articlementioning

confidence: 99%

A functional role for semaphorin 4D/plexin B1 interactions in epithelial branching morphogenesis during organogenesis

et al. 2008

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Semaphorins and their receptors, plexins, carry out important functions during development and disease. In contrast to the wellcharacterized plexin A family, however, very little is known about the functional relevance of B-type plexins in organogenesis, particularly outside the nervous system. Here, we demonstrate that plexin B1 and its ligand Sema4d are selectively expressed in epithelial and mesenchymal compartments during key steps in the genesis of some organs. This selective expression suggests a role in epithelial-mesenchymal interactions. Importantly, using the developing metanephros as a model system, we have observed that endogenously expressed and exogenously supplemented Sema4d inhibits branching morphogenesis during early stages of development of the ureteric collecting duct system. Our results further suggest that the RhoA-ROCK pathway, which is activated downstream of plexin B1, mediates these inhibitory morphogenetic effects of Sema4d and suppresses branch-promoting signalling effectors of the plexin B1 signalling complex. Finally, mice that lack plexin B1 show early anomalies in kidney development in vivo. These results identify a novel function for plexin B1 as a negative regulator of branching morphogenesis during kidney development, and suggest that the Sema4d-plexin B1 ligand-receptor pair contributes to epithelial-mesenchymal interactions during organogenesis via modulation of RhoA signalling.

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“…37 The plexin-B1 knockout mouse was recently reported. 41 The mice appear to develop normally. Studies on their platelets are pending.…”

Section: Receptor-ligand Interactions At the Junctions Between Plateletsmentioning

confidence: 99%

Novel Therapeutic Targets at the Platelet Vascular Interface

Brass

Zhu

Stalker

2008

ATVB

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Abstract-Platelet activation in vivo can be part of the hemostatic response to injury or a pathological response to disease.In either setting, platelets adhere to the vessel wall and to each other, forming a closely packed mass interspersed with fibrin. Recent studies have identified new molecules on the platelet surface and within platelets that support and regulate thrombus growth and stability, ensuring that platelet accumulation after injury is sufficient to stop bleeding, but not so exuberant that vascular occlusion occurs. An understanding of how this balance is achieved helps to illuminate the events of platelet activation and, at the same time, provides potential targets for new classes of antiplatelet agents.

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Plexin-B1 plays a redundant role during mouse development and in tumour angiogenesis

Cited by 72 publications

References 42 publications

Hypoxia-inducible Factor-1-mediated Regulation of Semaphorin 4D Affects Tumor Growth and Vascularity

Hypoxia-inducible Factor-1-mediated Regulation of Semaphorin 4D Affects Tumor Growth and Vascularity

A functional role for semaphorin 4D/plexin B1 interactions in epithelial branching morphogenesis during organogenesis

Novel Therapeutic Targets at the Platelet Vascular Interface

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