Neuropilin-2 Expression Promotes TGF-β1-Mediated Epithelial to Mesenchymal Transition in Colorectal Cancer Cells

Grandclement, Camille; Pallandre, Jean René; Degano, Séverine Valmary; Viel, E.; Bouard, Adeline; Balland, Jérémy; Rémy-Martin, Jean-Paul; Benoit, Sandrine; Rouleau, Alain; Boireau, Wilfrid; Klagsbrun, Michael; Ferrand, Christophe; Borg, Christophe

doi:10.1371/journal.pone.0020444

Cited by 86 publications

(105 citation statements)

References 46 publications

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“…Other authors have reported similar findings in studies of Nrp1 [35] and Nrp2 [36]. In view of these findings, we hypothesize that Nrp1 plays a key role on the membrane of cells by capturing active or latent TGF-β1, activating the latent form, and enhancing TGF-β-receptor signaling.…”

Section: Role Of Nrps In Cancersupporting

confidence: 87%

Neuropilins are multifunctional coreceptors involved in tumor initiation, growth, metastasis and immunity

2012

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The neuropilins (Nrps) are multifunctional proteins involved in development, immunity and cancer. Neuropilin-1 (Nrp1), or its homologue neuropilin-2 (Nrp2), are coreceptors that enhance responses to several growth factors (GFs) and other mediators. Nrps are coreceptors for the class 3 semaphorins (SEMA3), involved in axonal guidance, and several members of the vascular endothelial growth factor (VEGF) family. However, recent findings reveal they have a much broader spectrum of activity. They bind transforming growth factor β1 (TGF-β1) and its receptors, hepatocyte growth factor (HGF) and its receptor (cMet), platelet derived growth factor (PDGF) and its receptors, fibroblast growth factors (FGFs), and integrins. Nrps also promote Hedgehog signaling. These ligands and pathways are all relevant to angiogenesis and wound healing. In the immune system, the Nrps are expressed primarily by dendritic cells (DCs) and regulatory T cells (Tregs), and exert mainly inhibitory effects. In cancer, Nrps have been linked to a poor prognosis, which is consistent with their numerous interactions with ligands and receptors that promote tumor progression. We hypothesize that Nrps boost responses by capturing ligands, regulating GF receptor expression, endocytosis and recycling, and possibly also by signaling independently. Importantly, they promote epithelial-mesenchymal transition (EMT), and the survival of cancer stem cells. The recent finding that Nrps bind and internalize cell-penetrating peptides (CPPs) with arginine/lysine-rich C-terminal motifs (C-end rule; e.g., RXXR) is of interest. These CPPs can be coupled to large drugs for cancer therapy. Almost all studies have been preclinical, but findings suggest Nrps are excellent targets for anti-cancer drug development.

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Section: Role Of Nrps In Cancersupporting

confidence: 87%

Neuropilins are multifunctional coreceptors involved in tumor initiation, growth, metastasis and immunity

2012

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“…Although we have assessed downstream targets of the VEGF pathway and seen no changes, additional downstream effectors may still be contributing to melanoma cell proliferation. Recent studies have identified NRP2 expression as affecting the β-catenin and transforming growth factor-β1 pathways in human gastrointestinal and colorectal cancers, respectively [32,33]. As β-catenin and transforming growth factor-β1 have been implicated in melanoma tumorigenesis [34,35], these pathways may also be relevant to our current observations.…”

Section: Discussionsupporting

confidence: 57%

Neuropilin-2 promotes melanoma growth and progression in vivo

et al. 2016

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Tumor cell interactions with their microenvironment, and neighboring endothelial cells in particular, are critical for tumor cell survival and the metastatic process. Within the spectrum of tumors, melanomas are notorious for their ability to metastasize at a relatively early stage of development; however, little is known about the molecular pathways mediating this process. We recently performed a screen to assess critical mediators of melanoma metastasis by evaluating melanoma-endothelial cell communication. Neuropilin-2 (NRP2), a cell surface receptor involved in angiogenesis and axonal guidance, was found to be an important mediator of melanoma-endothelial cell cross-talk in these studies. Here we seek to further define the role of NRP2 in melanoma growth and progression. We use stable gene silencing of NRP2 in melanomas from varying stages of tumor progression to define the role of NRP2 in melanoma growth, migration, invasion, and metastasis. We found that NRP2 gene silencing in metastatic melanoma cell lines inhibited tumor cell growth in vitro; furthermore, knockdown of NRP2 expression in the metastatic melanoma cell line 1205Lu significantly inhibited in-vivo tumor growth and metastasis. We conclude that NRP2 plays an important role in mediating melanoma growth and metastasis and suggest that targeting this cell surface molecule may represent a significant therapeutic strategy for patients diagnosed with aggressive forms of melanoma.

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“…These expression data were substantiated by our finding that VEGF/NRP2 signaling regulates the expression of Bmi-1, a Polycomb group transcriptional repressor implicated in prostate tumorigenesis (16). Although a previous study had foreshadowed a role for NRP2 in the xenograft growth of colorectal carcinoma cells (37), our study is the first to demonstrate that an oncogenic pathway, i.e., c-Jun activation induced by PTEN loss, regulates NRP2. Moreover, our finding that NRP2 expression increases with Gleason grade is consistent with our previous finding that VEGF expression in cancer cells also increases with Gleason grade (20), supporting the hypothesis that autocrine VEGF/NRP2 signaling is characteristic of high-grade, aggressive prostate cancer.…”

Section: Discussionmentioning

confidence: 56%

VEGF/Neuropilin-2 Regulation of Bmi-1 and Consequent Repression of IGF-IR Define a Novel Mechanism of Aggressive Prostate Cancer

et al. 2012

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We demonstrate that the VEGF receptor, neuropilin-2 (NRP2) is associated with high-grade, PTEN-null prostate cancer and that its expression in tumor cells is induced by PTEN loss as a consequence of c-Jun activation. VEGF/NRP2 signaling represses IGF-1R expression and signaling and the mechanism involves Bmi-1-mediated transcriptional repression of the IGF-1R. This mechanism has significant functional and therapeutic implications that were evaluated. IGF-1R expression correlates with PTEN and inversely with NRP2 in prostate tumors. NRP2 is a robust biomarker for predicting response to IGF-1R therapy because prostate carcinomas that express NRP2 exhibit low levels of IGF-1R. Conversely, targeting NRP2 is only modestly effective because NRP2 inhibition induces compensatory IGF-1R signaling. Inhibition of both NRP2 and IGF-1R, however, completely blocks tumor growth in vivo.

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Neuropilin-2 Expression Promotes TGF-β1-Mediated Epithelial to Mesenchymal Transition in Colorectal Cancer Cells

Cited by 86 publications

References 46 publications

Neuropilins are multifunctional coreceptors involved in tumor initiation, growth, metastasis and immunity

Neuropilins are multifunctional coreceptors involved in tumor initiation, growth, metastasis and immunity

Neuropilin-2 promotes melanoma growth and progression in vivo

VEGF/Neuropilin-2 Regulation of Bmi-1 and Consequent Repression of IGF-IR Define a Novel Mechanism of Aggressive Prostate Cancer

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