Blocking Neuropilin-1 Function Has an Additive Effect with Anti-VEGF to Inhibit Tumor Growth

Pan, Qi; Chanthery, Yvan H.; Liang, Wei-Ching; Stawicki, Scott; Mak, Judy; Rathore, Nisha; Tong, Raymond K.; Kowalski, Joe; Yee, Sharon; Pacheco, Glenn; Ross, Sarajane; Cheng, Zhiyong; Couter, Jennifer Le; Plowman, Gregory D.; Peale, Franklin; Koch, Alexander W.; Wu, Yan; Bagri, Anil; Tessier‐Lavigne, Marc; Watts, Ryan J.

doi:10.1016/j.ccr.2006.10.018

Cited by 493 publications

(583 citation statements)

References 55 publications

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“…A humanized anti-VEGF antibody (Avastin V R ; Genentech, Inc.) is currently approved for treatment of multiple human cancers. The anti-NRP1 B antibody blocks VEGF binding to the NRP1 receptor and has been shown to inhibit vascular sprouting (34) and have an additive effect with anti-VEGF in inhibiting tumor growth (35). In this study, both therapies exhibited significant effects on blood volume and Q of varying degrees.…”

mentioning

confidence: 71%

“…The anti-VEGF molecule used in this study is known to be a potent antibody to VEGF and has previously been shown to inhibit tumor growth (31), reduce vascular density (7), and reduce the dynamic contrast-enhanced-MRI parameter K trans (33). The second molecule used in this study, anti-NRP1 B , has also been shown to inhibit vascular density (34) and to slow tumor growth when used in combination with anti-VEGF (35). The comparison of the vascular effects of these two molecules demonstrates that this MRI vascular imaging technique is capable of detecting statistically significant results for both strong angiogenic inhibitors and more subtle antiangiogenic antibodies.…”

Section: Discussionmentioning

confidence: 99%

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Vessel imaging with viable tumor analysis for quantification of tumor angiogenesis

Ungersma

Pacheco²,

et al. 2010

Magnetic Resonance in Med

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Imaging of tumor microvasculature has become an important tool for studying angiogenesis and monitoring antiangiogenic therapies. Ultrasmall paramagnetic iron oxide contrast agents for indirect imaging of vasculature offer a method for quantitative measurements of vascular biomarkers such as vessel size index, blood volume, and vessel density. Here, this technique is validated with direct comparisons to ex vivo micro-CT angiography and histologic vessel measurements, showing significant correlations between in vivo vascular MRI measurements and ex vivo structural vessel measurements. The sensitivity of the MRI vascular parameters is also demonstrated, in combination with a multispectral analysis technique for segmenting tumor tissue to restrict the analysis to viable tumor tissue and exclude regions of necrosis. It is shown that this viable tumor segmentation increases sensitivity for detection of significant effects on blood volume and vessel density by two antiangiogenic therapeutics (anti-VEGF and anti-neuropilin-1) on an HM7 colorectal tumor model. Anti-VEGF reduced blood volume by 36 6 3% (P < 0.0001) and vessel density by 52 6 3% (P < 0.0001) at 48 h posttreatment; the effects of anti-neuropilin-1 were roughly half as strong with a reduction in blood volume of 18 6 6% (P < 0.05) and a reduction in vessel density of 33 6 5% (P < 0.05) at 48 h posttreatment.

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confidence: 71%

Section: Discussionmentioning

confidence: 99%

Vessel imaging with viable tumor analysis for quantification of tumor angiogenesis

Ungersma

Pacheco²,

et al. 2010

Magnetic Resonance in Med

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“…Recently, several anti-neuropilin-1 agents that blocked VEGF binding were tested in animal models (Pan et al, 2007). Our findings on GBM cells suggest an additional role for neuropilin-1, in which it acts as a Sema3A receptor and facilitates tumor cell dispersal.…”

Section: Discussionmentioning

confidence: 65%

Autocrine semaphorin 3A signaling promotes glioblastoma dispersal

et al. 2009

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Glioblastoma multiforme (GBM) is the most malignant glioma type with diffuse borders due to extensive tumor cell infiltration. Therefore, understanding the mechanism of GBM cell dispersal is critical for developing effective therapies to limit infiltration. We identified neuropilin-1 as a mediator of cancer cell invasion by a functional proteomic screen and showed its role in GBM cells. Neuropilin-1 is a receptor for semaphorin3A (Sema3A), a secreted chemorepellent that facilitates axon guidance during neural development. Although neuropilin-1 expression in GBMs was previously shown, its role as a Sema3A receptor remained elusive. Using fluorophore-assisted light inactivation and RNA interference , we showed that neuropilin-1 is required for GBM cell migration. We also showed that GBM cells secrete Sema3A endogenously, and RNA interferencemediated downregulation of Sema3A inhibits migration and alters cell morphology that is dependent on Rac1 activity. Sema3A depletion also reduces dispersal, which is recovered by supplying Sema3A exogenously. Extracellular application of Sema3A decreases cell-substrate adhesion in a neuropilin-1-dependent manner. Using immunohistochemistry, we showed that Sema3A is overexpressed in a subset of human GBMs compared with the non-neoplastic brain. Together, these findings implicate Sema3A as an autocrine signal for neuropilin-1 to promote GBM dispersal by modulating substrate adhesion and suggest that targeting Sema3A-neuropilin-1 signaling may limit GBM infiltration.

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“…Recently, peptidic antagonists of NRP1 have been successfully used to block Sema3A signaling (Williams et al, 2005). Moreover, function blocking antibodies to NRP1 reduce tumor growth (Pan et al, 2007), and selective inhibitors of Sema3A improve nerve regeneration (Kaneko et al, 2006). The hydrophobic character of the pTM-NRP1 offers a unique chance to target naturally the heart of the cell membrane and thereby to increase the probability of inter-action with the protein domains to modulate.…”

Section: Discussionmentioning

confidence: 99%

Transmembrane Domain Interactions Control Biological Functions of Neuropilin-1

Roth

Nasarre

Dirrig‐Grosch

et al. 2008

MBoC

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Neuropilin-1 (NRP1) is a transmembrane receptor playing a pivotal role in the control of semaphorins and VEGF signaling pathways. The exact mechanism controlling semaphorin receptor complex formation is unknown. A structural analysis and modeling of NRP1 revealed a putative dimerization GxxxG motif potentially important for NRP1 dimerization and oligomerization. Our data show that this motif mediates the dimerization of the transmembrane domain of NRP1 as demonstrated by a dimerization assay (ToxLuc assay) performed in natural membrane and FRET analysis. A synthetic peptide derived from the transmembrane segment of NRP1 abolished the inhibitory effect of Sema3A. This effect depends on the capacity of the peptide to interfere with NRP1 dimerization and the formation of oligomeric complexes. Mutation of the GxxxG dimerization motif in the transmembrane domain of NRP1 confirmed its biological importance for Sema3A signaling. Overall, our results shed light on an essential step required for semaphorin signaling and provide novel evidence for the crucial role of transmembrane domain of bitopic protein containing GxxxG motif in the formation of receptor complexes that are a prerequisite for cell signaling.

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Blocking Neuropilin-1 Function Has an Additive Effect with Anti-VEGF to Inhibit Tumor Growth

Cited by 493 publications

References 55 publications

Vessel imaging with viable tumor analysis for quantification of tumor angiogenesis

Vessel imaging with viable tumor analysis for quantification of tumor angiogenesis

Autocrine semaphorin 3A signaling promotes glioblastoma dispersal

Transmembrane Domain Interactions Control Biological Functions of Neuropilin-1

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