Netrin‐4 is upregulated in breast carcinoma effusions compared to corresponding solid tumors

Yuan, Yuan; Leszczynska, Magdalena; Konstantinovsky, Sophya; Tropé, Claes G.; Reich, Reuven; Davidson, Ben

doi:10.1002/dc.21424

Cited by 18 publications

(13 citation statements)

References 21 publications

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“…These genes are Peroxidasin ( PXDN ), Netrin 4 ( NTN4 ) and GLIS Family Zinc Finger 3 ( GLIS3 ). The expression of PXDN , NTN4 and GLIS3 are all associated with motility, however these genes have not been previously described as modulators of EMT and invasion in melanoma and have not been evaluated for their potential for contributing to invasion [31–33]. …”

Section: Resultsmentioning

confidence: 99%

“…In cancers, the expression and functional role of NTN4 has been controversial. Recent studies have suggested a role for NTN4 in regulating metastasis, angiogenesis and tumor growth [31, 58]. However, other studies examining expression of NTN4 in clinical samples have reported that it is markedly down-regulated in prostate, breast and cervical cancers [59–61].…”

Section: Discussionmentioning

confidence: 99%

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Identifying and targeting determinants of melanoma cellular invasion

et al. 2016

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Epithelial-to-mesenchymal transition is a critical process that increases the malignant potential of melanoma by facilitating invasion and dissemination of tumor cells. This study identified genes involved in the regulation of cellular invasion and evaluated whether they can be targeted to inhibit melanoma invasion. We identified Peroxidasin (PXDN), Netrin 4 (NTN4) and GLIS Family Zinc Finger 3 (GLIS3) genes consistently elevated in invasive mesenchymal-like melanoma cells. These genes and proteins were highly expressed in metastatic melanoma tumors, and gene silencing led to reduced melanoma invasion in vitro. Furthermore, migration of PXDN, NTN4 or GLIS3 siRNA transfected melanoma cells was inhibited following transplantation into the embryonic chicken neural tube compared to control siRNA transfected melanoma cells. Our study suggests that PXDN, NTN4 and GLIS3 play a functional role in promoting melanoma cellular invasion, and therapeutic approaches directed toward inhibiting the action of these proteins may reduce the incidence or progression of metastasis in melanoma patients.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Identifying and targeting determinants of melanoma cellular invasion

et al. 2016

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“…Endogenous NTN4 also induces migration and proliferation in gastric cancer cells [21]. In breast carcinoma, NTN4 expression is most commonly detected in solid tumors than in malignant pleural effusions [22]. Combined, these findings suggest a possible biological role for NTN4 in tumor metastasis.…”

Section: Introductionmentioning

confidence: 99%

The Netrin-4/ Neogenin-1 axis promotes neuroblastoma cell survival and migration

et al. 2016

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Neogenin-1 (NEO1) is a transmembrane receptor involved in axonal guidance, angiogenesis, neuronal cell migration and cell death, during both embryonic development and adult homeostasis. It has been described as a dependence receptor, because it promotes cell death in the absence of its ligands (Netrin and Repulsive Guidance Molecule (RGM) families) and cell survival when they are present. Although NEO1 and its ligands are involved in tumor progression, their precise role in tumor cell survival and migration remain unclear. Public databases contain extensive information regarding the expression of NEO1 and its ligands Netrin-1 (NTN1) and Netrin-4 (NTN4) in primary neuroblastoma (NB) tumors. Analysis of this data revealed that patients with high expression levels of both NEO1 and NTN4 have a poor survival rate. Accordingly, our analyses in NB cell lines with different genetic backgrounds revealed that knocking-down NEO1 reduces cell migration, whereas silencing of endogenous NTN4 induced cell death. Conversely, overexpression of NEO1 resulted in higher cell migration in the presence of NTN4, and increased apoptosis in the absence of ligand. Increased apoptosis was prevented when utilizing physiological concentrations of exogenous Netrin-4. Likewise, cell death induced after NTN4 knock-down was rescued when NEO1 was transiently silenced, thus revealing an important role for NEO1 in NB cell survival. In vivo analysis, using the chicken embryo chorioallantoic membrane (CAM) model, showed that NEO1 and endogenous NTN4 are involved in tumor extravasation and metastasis. Our data collectively demonstrate that endogenous NTN4/NEO1 maintain NB growth via both pro-survival and pro-migratory molecular signaling.

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“…As such, there is currently interest in their potential as targets for cancer therapies [3,43]. There are only a few reports on the expression of Netrin-4 in human cancer [44-46] although Netrin-4 has been recently identified as a gene up-regulated in 37.5% of breast cancers and its expression is correlated with longer overall survival [45]. We reported previously that Netrin-4 overexpression in pancreatic tumor cells (PC3) [17] and in colon cancer cells (LS174) [18] delayed tumor angiogenesis in two mouse models of subcutaneous xenograft.…”

Section: Discussionmentioning

confidence: 99%

Netrin-4 promotes mural cell adhesion and recruitment to endothelial cells

et al. 2014

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Netrins are secreted molecules involved in axon guidance and angiogenesis. We previously showed that Netrin-4 acts as an anti-angiogenic factor by inhibiting endothelial cell (EC) functions. In this study, we investigated the effects of Netrin-4 on vascular smooth muscle cell (VSMC) activity in vitro and in vivo. We show that exogenous Netrin-4 stimulated VSMC adhesion and migration, and increased their coverage on EC tubes (grown on a Matrigel substrate). siRNA knock-down of endogenous Netrin-4 expression in VSMC decreased their recruitment to EC tubes. VSMC expressed Netrin-4 and three of the six Netrin-1 cognate receptors: DCC, Neogenin, and Unc5B. Silencing of these receptors reduced Netrin-4 adhesion to VSMC, strongly suggesting that these receptors were involved in the recruitment process. We previously showed that Netrin-4 overexpression in PC3 cancer cells delayed tumor growth in a model of subcutaneous xenograft by reducing tumor vessel density. Here, we show that Netrin-4 overexpression improved tumor blood vessel structure and increased VSMC coverage. Thus, Netrin-4 induced mural cell recruitment may play a role in the inhibition of tumor growth. Our data suggest that Netrin-4 is important for blood vessel normalization through the regulation of both endothelial and perivascular cells.

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Netrin‐4 is upregulated in breast carcinoma effusions compared to corresponding solid tumors

Cited by 18 publications

References 21 publications

Identifying and targeting determinants of melanoma cellular invasion

Identifying and targeting determinants of melanoma cellular invasion

The Netrin-4/ Neogenin-1 axis promotes neuroblastoma cell survival and migration

Netrin-4 promotes mural cell adhesion and recruitment to endothelial cells

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