Showing papers on "Neuropilins published in 2011"

Signal transduction by vascular endothelial growth factor receptors.

Abstract: VEGFs (vascular endothelial growth factors) control vascular development during embryogenesis and the function of blood vessels and lymphatic vessels in the adult. There are five related mammalian ligands, which act through three receptor tyrosine kinases. Signalling is modulated through neuropilins, which act as VEGF co-receptors. Heparan sulfate and integrins are also important modulators of VEGF signalling. Therapeutic agents that interfere with VEGF signalling have been developed with the aim of decreasing angiogenesis in diseases that involve tissue growth and inflammation, such as cancer. The present review will outline the current understanding and consequent biology of VEGF receptor signalling.

Class 3 semaphorins influence oligodendrocyte precursor recruitment and remyelination in adult central nervous system

Abstract: Oligodendrocyte precursor cells, which persist in the adult central nervous system, are the main source of central nervous system remyelinating cells. In multiple sclerosis, some demyelinated plaques exhibit an oligodendroglial depopulation, raising the hypothesis of impaired oligodendrocyte precursor cell recruitment. Developmental studies identified semaphorins 3A and 3F as repulsive and attractive guidance cues for oligodendrocyte precursor cells, respectively. We previously reported their increased expression in experimental demyelination and in multiple sclerosis. Here, we show that adult oligodendrocyte precursor cells, like their embryonic counterparts, express class 3 semaphorin receptors, neuropilins and plexins and that neuropilin expression increases after demyelination. Using gain and loss of function experiments in an adult murine demyelination model, we demonstrate that semaphorin 3A impairs oligodendrocyte precursor cell recruitment to the demyelinated area. In contrast, semaphorin 3F overexpression accelerates not only oligodendrocyte precursor cell recruitment, but also remyelination rate. These data open new avenues to understand remyelination failure and promote repair in multiple sclerosis.

Neuropilin-2 expression promotes TGF-β1-mediated epithelial to mesenchymal transition in colorectal cancer cells.

Abstract: Neuropilins, initially characterized as neuronal receptors, act as co-receptors for cancer related growth factors and were recently involved in several signaling pathways leading to cytoskeletal organization, angiogenesis and cancer progression. Then, we sought to investigate the ability of neuropilin-2 to orchestrate epithelial-mesenchymal transition in colorectal cancer cells. Using specific siRNA to target neuropilin-2 expression, or gene transfer, we first observed that neuropilin-2 expression endows HT29 and Colo320 for xenograft formation. Moreover, neuropilin-2 conferred a fibroblastic-like shape to cancer cells, suggesting an involvement of neuropilin-2 in epithelial-mesenchymal transition. Indeed, the presence of neuropilin-2 in colorectal carcinoma cell lines was correlated with loss of epithelial markers such as cytokeratin-20 and E-cadherin and with acquisition of mesenchymal molecules such as vimentin. Furthermore, we showed by surface plasmon resonance experiments that neuropilin-2 is a receptor for transforming-growth factor-β1. The expression of neuropilin-2 on colon cancer cell lines was indeed shown to promote transforming-growth factor-β1 signaling, leading to a constitutive phosphorylation of the Smad2/3 complex. Treatment with specific TGFβ-type1 receptor kinase inhibitors restored E-cadherin levels and inhibited in part neuropilin-2-induced vimentin expression, suggesting that neuropilin-2 cooperates with TGFβ-type1 receptor to promote epithelial-mesenchymal transition in colorectal cancer cells. Our results suggest a direct role of NRP2 in epithelial-mesenchymal transition and highlight a cross-talk between neuropilin-2 and TGF-β1 signaling to promote cancer progression. These results suggest that neuropilin-2 fulfills all the criteria of a therapeutic target to disrupt multiple oncogenic functions in solid tumors.

Neuropilins: A New Target for Cancer Therapy

Abstract: Recent investigations highlighted strong similarities between neural crest migration during embryogenesis and metastatic processes. Indeed, some families of axon guidance molecules were also reported to participate in cancer invasion: plexins/semaphorins/neuropilins, ephrins/Eph receptors, netrin/DCC/UNC5. Neuropilins (NRPs) are transmembrane non tyrosine-kinase glycoproteins first identified as receptors for class-3 semaphorins. They are particularly involved in neural crest migration and axonal growth during development of the nervous system. Since many types of tumor and endothelial cells express NRP receptors, various soluble molecules were also found to interact with these receptors to modulate cancer progression. Among them, angiogenic factors belonging to the Vascular Endothelial Growth Factor (VEGF) family seem to be responsible for NRP-related angiogenesis. Because NRPs expression is often upregulated in cancer tissues and correlated with poor prognosis, NRPs expression might be considered as a prognostic factor. While NRP1 was intensively studied for many years and identified as an attractive angiogenesis target for cancer therapy, the NRP2 signaling pathway has just recently been studied. Although NRP genes share 44% homology, differences in their expression patterns, ligands specificities and signaling pathways were observed. Indeed, NRP2 may regulate tumor progression by several concurrent mechanisms, not only angiogenesis but lymphangiogenesis, epithelial-mesenchymal transition and metastasis. In view of their multiples functions in cancer promotion, NRPs fulfill all the criteria of a therapeutic target for innovative anti-tumor therapies. This review focuses on NRP-specific roles in tumor progression.

Neuropilins are positive regulators of Hedgehog signal transduction

Abstract: The Hedgehog (Hh) pathway is essential for vertebrate embryogenesis, and excessive Hh target gene activation can cause cancer in humans. Here we show that Neuropilin 1 (Nrp1) and Nrp2, transmembrane proteins with roles in axon guidance and vascular endothelial growth factor (VEGF) signaling, are important positive regulators of Hh signal transduction. Nrps are expressed at times and locations of active Hh signal transduction during mouse development. Using cell lines lacking key Hh pathway components, we show that Nrps mediate Hh transduction between activated Smoothened (Smo) protein and the negative regulator Suppressor of Fused (SuFu). Nrp1 transcription is induced by Hh signaling, and Nrp1 overexpression increases maximal Hh target gene activation, indicating the existence of a positive feedback circuit. The regulation of Hh signal transduction by Nrps is conserved between mammals and bony fish, as we show that morpholinos targeting the Nrp zebrafish ortholog nrp1a produce a specific and highly penetrant Hh pathway loss-of-function phenotype. These findings enhance our knowledge of Hh pathway regulation and provide evidence for a conserved nexus between Nrps and this important developmental signaling system.

Multifaceted role of neuropilins in cancer

Abstract: Neuropilins comprise two homologous widely-expressed single-pass plasma membrane receptors (Nrp1 and Nrp2), originally identified for binding secreted Semaphorins and Vascular Endothelial Growth Factors (in association with Plexins and VEGF-Receptors). Semaphorins have been implicated with opposite functions in cancer: either as putative tumor suppressors and anti-angiogenic factors, or mediating tumour angiogenesis, invasion and metastasis. Moreover, due to their implication in VEGF signaling, neuropilins regulate vascular development and tumor angiogenesis. Recent evidence further suggests a role of neuropilins in cancer progression due to their interaction with receptor tyrosine kinases, adhesion molecules, and integrins. Furthermore, neuropilins have been implicated in response to additional growth factors, such as Hepatocyte Growth Factor, Fibroblast Growth Factor, Transforming Growth Factor beta, Galectin, etc. Altogether, these data seem to qualify neuropilins as signaling platforms on the cell surface, potentially capable of regulating cancer cells, as well as cells of the tumor microenvironment. Intriguingly, clinical-pathological data often indicate a correlation between increased expression of neuropilins and advanced stage tumors with poor prognosis. In this article, we will review the current experimental evidence about the functional role of neuropilins in cancer and the underlying molecular mechanisms.

Expression of class 3 semaphorins and their receptors in human breast neoplasia

Abstract: Staton C A, Shaw L A, Valluru M, Hoh L, Koay I, Cross S S, Reed M W & Brown N J (2011) Histopathology59, 274–282 Expression of class 3 semaphorins and their receptors in human breast neoplasia Aims: This study aimed to identify the involvement of class 3 semaphorins (Sema3) and receptors, neuropilins (Np1 and Np2) and plexins (A1–A4) in breast cancer development and angiogenesis. Methods and results: We quantified and correlated Sema3A, Sema3B, Sema3F and their known receptors and coreceptors Plexin-A1, Plexin-A3, Np1 and Np2 in sections of normal human breast, benign and pre-malignant hyperplastic tissue, pre-invasive and invasive cancer, and compared these findings with our previously published data on vascular endothelial growth factor (VEGF) and microvessel density (MVD) in the same samples. Histological analysis revealed that Sema3B was expressed more strongly and widely than Sema3A and 3F in normal breast tissue and all three semaphorins decreased with the transition from in situ to invasive cancer (P < 0.014). Plexin-A3 decreased significantly with progression towards invasive cancer (P < 0.045), whereas Plexin-A1 expression was only significantly reduced once invasion had occurred (P = 0.012). Np1 and Np2 were expressed in both endothelial and epithelial/tumour cells. Np2 expression did not change, but Np1 expression significantly increased in the spectrum from hyperplasia to ductal carcinoma in situ (P < 0.035), but decreased with invasive cancer. Conclusion: These data suggest that a decrease in class 3 semaphorin and their plexin receptors have some relationship with disease progression in ductal breast carcinoma.

A role for class 3 semaphorins in prostate cancer.

Abstract: BACKGROUND Class 3 semaphorins are secreted proteins that act as guidance cues for migrating cells via their transmembrane receptors plexins and neuropilins. Semaphorins have a role in cancer affecting tumor progression both directly, and indirectly by affecting angiogenesis. METHODS The expression of semaphorins and their receptors in prostate cancer cell lines and tissue was determined by RT-PCR, Western blotting and immunohistochemistry. The effect of Sema3E on prostate cancer cell lines was determined by adhesion assays and transwell migration assays. RESULTS Semaphorins and their receptors, plexins and neuropilins, are widely co-expressed in prostate cancer cell lines and tissue with a significant overexpression of Sema3E in tumor tissue. Sema3E affected integrin-mediated adhesion to fibronectin of prostate cancer cells, and inhibited their motility. Expression of Sema3C was upregulated and Sema3A and Sema3E were down regulated in prostate cells by hypoxia, consistent with an additional role for Sema3A and 3E as anti-angiogenic factors in prostate cancer. CONCLUSIONS Semaphorin 3E is aberrantly expressed in prostate cancer and affects adhesion and motility of prostate cancer cells, indicating a role for the Sema3E/PlexinD1 signaling pathway in prostate cancer and identifying a new possible target for therapy. Prostate 71:649–658, 2011. © 2010 Wiley-Liss, Inc.

Class 3 semaphorins and their receptors in physiological and pathological angiogenesis.

Abstract: Class 3 semaphorins (Sema3) are a family of secreted proteins that were originally identified as axon guidance factors mediating their signal transduction by forming complexes with neuropilins and plexins. However, the wide expression pattern of Sema3 suggested additional functions other than those associated with the nervous system, and indeed many studies have now indicated that Sema3 proteins and their receptors play a role in angiogenesis. The present review specifically focuses on recent evidence for this role in both physiological and pathological angiogenesis.

Neuropilin-2 promotes branching morphogenesis in the mouse mammary gland.

Abstract: Although the neuropilins were characterized as semaphorin receptors that regulate axon guidance, they also function as vascular endothelial growth factor (VEGF) receptors and contribute to the development of other tissues. Here, we assessed the role of NRP2 in mouse mammary gland development based on our observation that NRP2 is expressed preferentially in the terminal end buds of developing glands. A floxed NRP2 mouse was bred with an MMTV-Cre strain to generate a mammary gland-specific knockout of NRP2. MMTV-Cre;NRP2loxP/loxP mice exhibited significant defects in branching morphogenesis and ductal outgrowth compared with either littermate MMTV-Cre;NRP2+/loxP or MMTV-Cre mice. Mechanistic insight into this morphological defect was obtained from a mouse mammary cell line in which we observed that VEGF165, an NRP2 ligand, induces branching morphogenesis in 3D cultures and that branching is dependent upon NRP2 as shown using shRNAs and a function-blocking antibody. Epithelial cells in the mouse mammary gland express VEGF, supporting the hypothesis that this NRP2 ligand contributes to mammary gland morphogenesis. Importantly, we demonstrate that VEGF and NRP2 activate focal adhesion kinase (FAK) and promote FAK-dependent branching morphogenesis in vitro. The significance of this mechanism is substantiated by our finding that FAK activation is diminished significantly in developing MMTV-Cre;NRP2loxP/loxP mammary glands compared with control glands. Together, our data reveal a VEGF/NRP2/FAK signaling axis that is important for branching morphogenesis and mammary gland development. In a broader context, our data support an emerging hypothesis that directional outgrowth and branching morphogenesis in a variety of tissues are influenced by signals that were identified initially for their role in axon guidance.

Plexin B1 inhibits integrin-dependent pp125FAK and Rho activity in melanoma.

Abstract: Semaphorins are secreted and membrane bound proteins that regulate axon guidance through receptors Plexins and neuropilins. Plexin B1, the Semaphorin 4D receptor, is a recently described tumor suppressor protein for melanoma. We recently showed that Plexin B1 abrogates activation of the oncogenic receptor, c-Met, by its ligand, hepatocyte growth factor (HGF), in melanoma. We have now investigated the effect of Plexin B1 on integrin-dependent pp125(FAK) activation, and the small GTP-binding protein Rho, in melanoma. Integrin receptors and Rho play critical roles in melanoma progression, through regulation of migration, proliferation and apoptosis. We engineered two human melanoma cell lines expressing Plexin B1 and analyzed integrin-dependent migration, integrin-dependent pp125(FAK) activation, and Rho activity. Results show that Plexin B1 abrogates integrin-dependent migration and activation of pp125(FAK). We also show that Rho activity is significantly reduced in cells expressing Plexin B1, and that Plexin B1 suppresses HGF-dependent Rho activation.

Placental growth factor: a tissue modelling factor with therapeutic potentials in neurology?

Abstract: Placental growth factor (PlGF) is an angiogenic factor that belongs to the vascular endothelial growth factor (VEGF) family. Besides its well known capacity to potentiate the angiogenic action of VEGF, PlGF also participates in inflammatory processes by attracting and activating monocytes; it plays therefore more specifically a role in pathological conditions. PIGF and its two receptors, VEGFR-1 and neuropilins (NRPs), are expressed in the brain and increase after experimental stroke, but their precise functions in the nervous system remain underexplored. In this review article, we summarize present knowledge on the role of PlGF in various nervous system disease processes. Given the available data, P1GF has neuroprotective and neurotrophic properties that make it an actor of considerable interest in the pathophysiology and potentially in the therapy of degenerative and traumatic brain or spinal cord diseases.

The reception and the party after: how vascular endothelial growth factor receptor 2 explores cytoplasmic space

Abstract: Summary Vascular endothelial growth factors (VEGFs) regulate blood and lymph vessel formation through activation of the type V receptor tyrosine kinases VEGFR-1, -2 and -3. In addition, VEGFs interact with co-receptors such as neuropilins, integrins, semaphorins or heparansulfate glycosaminoglycans. Ligand binding dimerises the receptors and activates their intracellular tyrosine kinase domains, resulting in phosphorylation of tyrosine residues acting as docking sites for intracellular signalling molecules. Ligand-induced receptor is internalised and then transported through early, late, and recycling endosomes, and finally degraded by proteasomal or lysosomal pathways. Biological output by VEGF is mediated through distinct receptor/co-receptor complexes and generates signals in all cellular compartments triggering cellular responses such as cell migration, cell proliferation, vessel formation and maturation, as well as changes in vessel fenestration, constriction and permeability. Here we review recent experiments showing how VEGFR-2 is transported through intracellular vesicular compartments specified by Rab family GTPases, and discuss how different VEGF-A isoforms specify intracellular receptor trafficking. We also discuss how the biological consequences of aberrant receptor trafficking bear on the development of vascular disease.

Monoclonal Antibody Against NRP-1 b1b2

Abstract: Neuropilin-1 is a member of the neuropilins family protein, which contains a large extracellular domain (a1a2, b1b2 and c), a single transmembrane domain, and a short cytoplasmic tail. NRP-1 plays a critical role in angiogenesis and stimulates endothelial cell division and migration by binding VEGF165 with b1b2 domain. In the present study, we report the establishment of a monoclonal antibody (A6-26-11-26 clone) specific for NRP-1 b1b2 through hybridoma method. Western blot analysis indicates that our NRP-1 b1b2 MAb can combine both NRP-1 b1b2 and NRP-1 originated from tumor cells. This monoclonal antibody against NRP-1 b1b2 will be useful in the further development of cancer target strategy.

Neuropilin and neuropilin associated molecules as new molecular targets in pancreatic adenocarcinoma.

Abstract: The Neuropilin receptors are increasingly recognized as receptors for vascular endothelial growth factors like VEGF-A and VEGF-C as well as other important growth factors like HGF and FGF in human vasculature and in tumor cells. More and more studies show an important role of Neuropilin in cancer biology suggesting that these transmembrane proteins might be an emerging target for new therapies in different subsets of cancer. Interestingly, blocking the adaptor protein GIPC1/Synectin that interacts with Neuropilin might be another interesting avenue for therapy. This review summarizes unfolding scientific data on these receptors and its interacting protein GIPC1/Synectin as molecular targets for therapy in pancreatic ductal adenocarcinoma.

Abstract 5131: Escape from breast cancer therapy, are neuropilins the key

Abstract: The anti-VEGF antibody Bevacizumab (Bz) inhibits VEGF binding to VEGF-R1/2 and increases progression free survival in breast cancer patients. However, eventually tumors escape treatment control and we hypothesize that this may be because Bz does not prevent VEGF from binding to its alternative receptors, the neuropilins (Np1 & Np2). Gene expression of VEGF 165 , VEGF 165b and the VEGF receptors, VEGF-R1/2, Np1 and Np2 in human dermal microvascular endothelial cells (ECs) and three breast cancer cell lines (MCF7, MDA-MB-231 & MDA-MB-436) was assessed using standard PCR techniques and protein expression by Western blot. The effects of 4 different Np1 binding peptides and Bz were assessed on EC differentiation (Matrigel assay of tubule formation), migration (scratch assay) and proliferation (MTS assay). PCR revealed that VEGF and Np1/Np2 are expressed in ECs and all three breast cancer cell lines whereas VEGF-R1/2 are expressed in ECs and MDA-MB-436/231 cells only. These data were also confirmed by Western blot analysis. EC differentiation when measured as tubule number or branch points was significantly inhibited (p These data show that endothelial and breast cancer cells express Np1/Np2 receptors, and one Np1 binding peptide (p10: GSGSTRPPRRRR) inhibits both EC differentiation and breast cancer cell proliferation, and potentially EC and breast cancer cell migration in vitro, suggesting that this peptide may have therapeutic potential for breast cancer treatment. In vivo studies are evaluating the response to Np1 inhibition (p10) alone and in combination with Bz on angiogenesis in a breast tumor model using subcutaneous implantation of either MDA-MB-231 or MDA-MB-436 cells. Supported by Breast Cancer Campaign Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5131. doi:10.1158/1538-7445.AM2011-5131