Neuropilin-2 Is Upregulated in Lung Cancer Cells during TGF-β1–Induced Epithelial–Mesenchymal Transition

Nasarre, Patrick; Gemmill, Robert M.; Potiron, Vincent; Roche, Joëlle; Lu, Xian; Barón, Anna E.; Korch, Christopher; Garrett‐Mayer, Elizabeth; Laganà, Alessandro; Howe, Philip H.; Drabkin, Harry A.

doi:10.1158/0008-5472.can-13-1755

Cited by 65 publications

(73 citation statements)

References 59 publications

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“…Previously, we demonstrated that local tumor invasion in subcutaneous xenografts was NRP2-dependent (17). To extend these results to the isoforms, we subcutaneously injected H358 cells with endogenous NRP2 knockdown and reexpression of shRNA-resistant NRP2a and NRP2b into immunodeficient mice.…”

Section: Resultsmentioning

confidence: 99%

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The neuropilin 2 isoform NRP2b uniquely supports TGFβ-mediated progression in lung cancer

et al. 2017

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Neuropilins (NRP1 and NRP2) are co-receptors for heparin-binding growth factors and class 3 semaphorins. Different isoforms of NRP1 and NRP2 are produced by alternative splicing. We found that in non–small cell lung cancer (NSCLC) cell lines, transforming growth factor–β (TGFβ) signaling preferentially increased the abundance of NRP2b. NRP2b and NRP2a differ only in their carboxyl-terminal regions. Although the presence of NRP2b inhibited cultured cell proliferation and primary tumor growth, NRP2b enhanced cellular migration, invasion into Matrigel, and tumorsphere formation in cultured cells in response to TGFβ signaling and promoted metastasis in xenograft mouse models. These effects of overexpressed NRP2b contrast with the effects of overexpressed NRP2a. Hepatocyte growth factor (HGF)–induced phosphorylation of the kinase AKT was specifically promoted by NRP2b, whereas inhibiting the HGF receptor MET attenuated NRP2b-dependent cell migration. Unlike NRP2a, NRP2b did not bind the PDZ domain scaffolding protein GAIP carboxyl terminus–interacting protein (GIPC1) and only weakly recruited phosphatase and tensin homolog (PTEN), potentially explaining the difference between NRP2b-mediated and NRP2a-mediated effects. Analysis of NSCLC patient tumors showed that NRP2b abundance correlated with that of the immune cell checkpoint receptor ligand PD-L1 as well as with epithelial-to-mesenchymal transition (EMT) phenotypes in the tumors, acquired resistance to epidermal growth factor receptor (EGFR) inhibitors, disease progression, and poor survival in patients. NRP2b knockdown attenuated the acquisition of resistance to the EGFR inhibitor gefitinib in cultured NSCLC cells. Thus, in NSCLC, NRP2b contributed to the oncogenic response to TGFβ and correlated with tumor progression in patients.

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Section: Resultsmentioning

confidence: 99%

“…We previously reported that NRP2 was up-regulated during TGFβ-mediated EMT in NSCLC cell lines and that NRP2 knockdown inhibited TGFβ-mediated responses, including invasive tumor growth (17). Notably, nearly all reported NRP2 studies have involved the prototype NRP2a isoform, which is closely related throughout its entirety to NRP1.…”

Section: Introductionmentioning

confidence: 99%

The neuropilin 2 isoform NRP2b uniquely supports TGFβ-mediated progression in lung cancer

et al. 2017

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“…34,35 However, the potential involvement of VEGF-C in NRP2-mediated phenotypes in these studies was not discussed.…”

Section: Vegf-c and Neurophilinmentioning

confidence: 98%

The non-canonical role of vascular endothelial growth factor-C axis in cancer progression

Wang

Tsai

2015

Exp Biol Med (Maywood)

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It has been shown in many clinical studies that the level of vascular endothelial growth factor-C (VEGF-C) positively correlates with lymph node metastasis. Nevertheless, beyond the canonical role of VEGF-C in stimulating lymphangiogenesis and thus promoting lymph node/distant metastasis, emerging evidence indicates that expression of VEGF-C contributes to various aspects of carcinogenicity via autocrine regulation. The newly identified functions of VEGF-C include but are not limited to proliferation, migration, invasion, and chemo-resistance. Besides tumor cell autocrine regulation, VEGF-C can also modulate the immune system such that tumor cells more easily escape immune surveillance. Therefore, understanding the functional roles and regulatory mechanisms related to the VEGF-C axis may lead to alternative strategies for cancer treatment. This mini-review will focus on summarizing recent discoveries regarding the unconventional functions of VEGF-C in cancer progression.

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“…51,52 Zinc finger E-boxebinding homeobox 1 and inhibitor of DNA-binding protein 2 have been shown to down-regulate SEMA3F in tumor cells, 30,53 but SEMA3F regulation in normal epithelial cells and its effects on ECs and vascular permeability are unclear.…”

Section: Discussionmentioning

confidence: 99%

Inflammation and Lymphedema Are Exacerbated and Prolonged by Neuropilin 2 Deficiency

Mucka

Levonyak

Geretti

et al. 2016

The American Journal of Pathology

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The vasculature influences the progression and resolution of tissue inflammation. Capillaries express vascular endothelial growth factor (VEGF) receptors, including neuropilins (NRPs), which regulate interstitial fluid flow. NRP2, a receptor of VEGFA and semaphorin (SEMA) 3F ligands, is expressed in the vascular and lymphatic endothelia. Previous studies have demonstrated that blocking VEGF receptor 2 attenuates VEGFA-induced vascular permeability. The inhibition of NRP2 was hypothesized to decrease vascular permeability as well. Unexpectedly, massive tissue swelling and edema were observed in Nrp2 À/À mice compared with wild-type littermates after delayed-type hypersensitivity reactions. Vascular permeability was twofold greater in inflamed blood vessels in Nrp2-deficient mice compared to those in Nrp2-intact littermates. The addition of exogenous SEMA3F protein inhibited vascular permeability in Balb/cJ mice, suggesting that the loss of endogenous Sema3F activity in the Nrp2-deficient mice was responsible for the enhanced vessel leakage. Functional lymphatic capillaries are necessary for draining excess fluid after inflammation; however, Nrp2-mutant mice lacked superficial lymphatic capillaries, leading to 2.5-fold greater fluid retention and severe lymphedema after inflammation. In conclusion, Nrp2 deficiency increased blood vessel permeability and decreased lymphatic vessel drainage during inflammation, highlighting the importance of the NRP2/SEMA3F pathway in the modulation of tissue swelling and resolution of postinflammatory edema. (Am J Pathol 2016 http://dx

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Neuropilin-2 Is Upregulated in Lung Cancer Cells during TGF-β1–Induced Epithelial–Mesenchymal Transition

Cited by 65 publications

References 59 publications

The neuropilin 2 isoform NRP2b uniquely supports TGFβ-mediated progression in lung cancer

The neuropilin 2 isoform NRP2b uniquely supports TGFβ-mediated progression in lung cancer

The non-canonical role of vascular endothelial growth factor-C axis in cancer progression

Inflammation and Lymphedema Are Exacerbated and Prolonged by Neuropilin 2 Deficiency

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