Neuropilin-2 interacts with VEGFR-2 and VEGFR-3 and promotes human endothelial cell survival and migration

Favier, Benoît; Alam, Antoine; Barron, Pauline; Bonnin, Jacques; Laboudie, Patricia; Fons, Pierre; Mandron, Marie; Hérault, Jean-Pascal; Neufeld, Gera; Savi, Pierre; Herbert, Jean‐Marc; Bono, Françoise

doi:10.1182/blood-2005-11-4447

Cited by 261 publications

(266 citation statements)

References 55 publications

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“…Sema3F overexpression has been shown to have a direct chemorepulsive effect on lymphatic endothelial cells [58]. Sema3F appears to compete for Nrp2 binding with VEGF-C and decreases endothelial cell survival and migration [92]. Nevertheless, direct evidence for an antilymphangiogenic role of Sema3F is limited.…”

Section: Lymphangiogenesis and Cancermentioning

confidence: 98%

Semaphorin signaling in angiogenesis, lymphangiogenesis and cancer

2011

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Angiogenesis, the formation of new blood vessels from preexisting vasculature, is essential for many physiological processes, and aberrant angiogenesis contributes to some of the most prevalent human diseases, including cancer. Angiogenesis is controlled by delicate balance between pro-and anti-angiogenic signals. While pro-angiogenic signaling has been extensively investigated, how developmentally regulated, naturally occurring anti-angiogenic molecules prevent the excessive growth of vascular and lymphatic vessels is still poorly understood. In this review, we summarize the current knowledge on how semaphorins and their receptors, plexins and neuropilins, control normal and pathological angiogenesis, with an emphasis on semaphorin-regulated anti-angiogenic signaling circuitries in vascular and lymphatic endothelial cells. This emerging body of information may afford the opportunity to develop novel anti-angiogenic therapeutic strategies.

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Section: Lymphangiogenesis and Cancermentioning

confidence: 98%

Semaphorin signaling in angiogenesis, lymphangiogenesis and cancer

2011

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“…Two groups of proangiogenic factors were decreased in IL12rb2 ϩ tumors, the first included molecules that have never been associated before to IL-12 (cadherin-5, laminin, ephrin A1, ephrin B2, ephrin receptor B4, FGF6, FGFR3, and neuropilin), the second encompassed molecules already related to IL-12 (angiopoietin 1 and 2, eotaxin, procollagen type XVIII␣1, cox1, MMP9, and sphyngosin kinase 1) (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42).…”

Section: Discussionmentioning

confidence: 99%

“…Thus, expression of cadherin-5, laminin, ephrin A1, ephrin B2, ephrin receptor B4, FGF6, FGFR3, and neuropilin, whose relationship with IL-12 has never been reported, was decreased. These molecules are expressed during tumor neovascularization and promote organization, survival or migration of endothelial cells (23)(24)(25)(26)(27)(28)(29)(30)(31). Other, IL-12-related proangiogenic molecules down-regulated in IL12rb2 ϩ vs. IL12rb2 Ϫ tumors were angiopoietin 1 and 2, eotaxin, procollagen type XVIII␣1, cox1, MMP9, and sphyngosin kinase 1 (32)(33)(34)(35)(36)(37)(38).…”

Section: Endogenous Il-12 Dampens Tumorigenicity Of B16 Melanoma Cellsmentioning

confidence: 99%

Endogenous IL-12 triggers an antiangiogenic program in melanoma cells

Airoldi

Carlo

Cocco

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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The IL12RB2 gene acts as a tumor suppressor in human B cell malignancies. Indeed, Il12rb2 knockout (KO) mice develop spontaneously B cell tumors, but also lung epithelial tumors. This latter phenotype may be related to (i) impairment of host IL-12-mediated immunosurveillance and/or (ii) IL-12 inability to inhibit directly the growth of IL-12 unresponsive malignant cells. To address this issue, we transplanted IL-12R ؉ B16 melanoma cells into syngeneic Il12rb2 KO mice with the following rationale: (i) these mice have severe defects in IFN-␥ production, as well as in cytotoxic T lymphocyte and natural killer cell cytotoxicity, and (ii) they produce but do not use IL-12 that can potentially bind to and target tumor cells only. Il12rb2 KO mice displayed higher endogenous serum levels of IL-12 and developed smaller B16 tumors than WT animals. These tumors showed reduced proliferation, increased apoptosis, and defective microvessel formation related to down-regulated expression of a set of proangiogenic genes previously unrelated to IL-12. Such effects depended on direct activity of endogenous IL-12 on tumor cells in KO mice, and hydrodynamic delivered IL-12 caused further reduced tumorigenicity of B16 cells in these mice. A previously undescribed mechanism of the IL-12 antitumor activity has been here identified and characterized.angiogenesis ͉ tumor immunology ͉ cytokines I nterleukin 12 is a heterodimeric cytokine bridging innate and adaptive immunity (1). IL-12, which belongs to a family of structurally related cytokines including IL-23 and IL-27 (2, 3), is formed by the IL12p35 and IL12p40 subunits (4) and binds to the IL-12R, composed of the ␤1 and the ␤2 chains. Both chains are needed for high affinity binding of the cytokine and initiation of signal transduction (5, 6). IL12p40 associates with the p19 subunit to form IL-23, which binds to a receptor composed of IL12R␤1 and IL-23R (2, 3). Therefore, the IL12p35 and the IL12R␤2 subunits are unique components of IL-12 and IL-12R, respectively. IL-12, which is produced predominantly by antigen-presenting cells, drives T helper (Th1) responses, enhances T and natural killer (NK) cell cytotoxicity, and induces IFN-␥ production by T and NK cells (4,[7][8][9]. In addition, we have shown that IL-12 contributes to the regulation of normal human B cell function through stimulation of IgM synthesis and IFN-␥ production (10).IL-12 exerts antitumor activity through IFN-␥-dependent and independent mechanisms (11-15), which include modulation of the immune system and antiangiogenesis (16)(17)(18). We have recently demonstrated that the IL12RB2 gene acts as a tumor suppressor in human chronic B cell malignancies (14) and, accordingly, that aging IL12rb2 knockout (KO) mice develop spontaneously B cell tumors. The same mice showed high incidence of lung epithelial tumors. This latter finding may be related to reduced immune surveillance, because of their deficient T and NK cell-mediated cytotoxicity (19), Th2-biased T cell differentiation (20), and/or lack of IL-12-mediated dir...

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“…In contrast to VEGFR2, accumulating evidence showed that VEGFR1 may mediate negative signals for angiogenesis and vascular leakage (7,19). In addition to the tyrosine kinase receptors, VEGF-A also binds to neuropilin-1 and -2, which are involved in the guidance of vessel formation and modulate vascular functions mediated by the high affinity tyrosine kinase receptors (20)(21)(22)(23)(24).…”

mentioning

confidence: 99%

Malignant cell-derived PlGF promotes normalization and remodeling of the tumor vasculature

Hedlund

Hosaka

Zhong

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Vascular functions of PlGF remain poorly understood and controversial. Here, we show that tumor cell-derived PlGF-1 and PlGF-2 displayed significant remodeling effects on the tumor vasculature, leading to a normalized vascular phenotype and improved functions against leakage. In two murine tumor models, that is, T241 fibrosarcoma and Lewis lung carcinoma, stable expression of PlGF-1 and PlGF-2 in tumor cells resulted in significant reduction of tumor microvascular density and branch formation. Markedly, the vasculature in PlGF-expressing tumors consisted of relatively large-diameter microvessels with substantial improvement of pericyte coverage. Similarly, PlGF-induced vascular normalization and remodeling were also observed in a spontaneous human choriocarcinoma that expressed endogenous PlGF. Our findings shed light on functions of PlGF as a vascular remodeling factor that normalizes the tumor vasculature and thus may have conceptual implications of cancer therapy. vascular permeability ͉ vascular remodeling

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Neuropilin-2 interacts with VEGFR-2 and VEGFR-3 and promotes human endothelial cell survival and migration

Cited by 261 publications

References 55 publications

Semaphorin signaling in angiogenesis, lymphangiogenesis and cancer

Semaphorin signaling in angiogenesis, lymphangiogenesis and cancer

Endogenous IL-12 triggers an antiangiogenic program in melanoma cells

Malignant cell-derived PlGF promotes normalization and remodeling of the tumor vasculature

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