Netrin-1 concentrations in patients with advanced gastric cancer and its relation with treatment

Kefeli, Umut; Yıldırım, Mehmet; Aydın, Dinçer; Madenci, Özlem Çakır; Yaşar, Nurgül; Sener, Nur; Mert, Aslıhan Güven; Yuksel, Sinemis; Ercelep, Özlem; Korkmaz, Taner; Yıldız, Ramazan; Gümüş, Mahmut

doi:10.3109/1354750x.2012.709882

Cited by 20 publications

(17 citation statements)

References 23 publications

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“…As a result, aspirin preserved the synthesis of secreted netrin-1 under pro-inflammatory conditions, thus counteracting monocyte/macrophage plaque accumulation. Future clinical investigations are needed to verify the applicability of these findings to human atherosclerosis, as well as to non-cardiovascular diseases including neurological disorders (Rajasekharan and Kennedy, 2009 ; Izzi and Charron, 2011 ) and cancer (Delloye-Bourgeois et al ., 2012 ; Kefeli et al ., 2012 ; Ko et al ., 2012 ) where aspirin has also been reported to exert protective actions (Algra and Rothwell, 2012 ; Rothwell et al ., 2014 ,b 2012a ).…”

Section: Discussionmentioning

confidence: 99%

Aspirin‐induced histone acetylation in endothelial cells enhances synthesis of the secreted isoform of netrin‐1 thus inhibiting monocyte vascular infiltration

Passacquale

Phinikaridou

Warboys

et al. 2015

British J Pharmacology

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Background and PurposeThere are conflicting data regarding whether netrin-1 retards or accelerates atherosclerosis progression, as it can lead either to monocyte repulsion from or retention within plaques depending on its cellular source. We investigated the effect of aspirin, which is widely used in cardiovascular prophylaxis, on the synthesis of different isoforms of netrin-1 by endothelial cells under pro-inflammatory conditions, and defined the net effect of aspirin-dependent systemic modulation of netrin-1 on atherosclerosis progression.Experimental ApproachNetrin-1 synthesis was studied in vitro using human endothelial cells stimulated with TNF-α, with or without aspirin treatment. In vivo experiments were conducted in ApoE−/− mice fed with a high-fat diet (HFD), receiving either aspirin or clopidogrel.Key ResultsTNF-α-induced NF-κB activation up-regulated the nuclear isoform of netrin-1, while simultaneously reducing secreted netrin-1. Down-regulation of the secreted isoform compromised the chemorepellent action of the endothelium against monocyte chemotaxis. Aspirin counteracted TNF-α-mediated effects on netrin-1 synthesis by endothelial cells through COX-dependent inhibition of NF-κB and concomitant histone hyperacetylation. Administration of aspirin to ApoE−/− mice on HFD increased blood and arterial wall levels of netrin-1 independently of its effects on platelets, accompanied by reduced plaque size and content of monocytes/macrophages, compared with untreated or clopidogrel-treated mice. In vivo blockade of netrin-1 enhanced monocyte plaque infiltration in aspirin-treated ApoE−/− mice.Conclusions and ImplicationsAspirin counteracts down-regulation of secreted netrin-1 induced by pro-inflammatory stimuli in endothelial cells. The aspirin-dependent increase of netrin-1 in ApoE−/− mice exerts anti-atherogenic effects by preventing arterial accumulation of monocytes.

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Section: Discussionmentioning

confidence: 99%

Aspirin‐induced histone acetylation in endothelial cells enhances synthesis of the secreted isoform of netrin‐1 thus inhibiting monocyte vascular infiltration

Passacquale

Phinikaridou

Warboys

et al. 2015

British J Pharmacology

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“…The involvement of netrin-1 in the spread of cancer cells was corroborated by the finding that especially metastatic breast carcinomas show netrin-1 overexpression compared to their non-metastatic counterparts [9]. However, since netrin-1 is strongly overexpressed in various cancer entities, it has been presented as a pluripotent tumor biomarker independent of the grade of malignancy or tumor subtype [10]–[12]. For some cancer subtypes such as adenocarcinomas of the pancreas, it was demonstrated that netrin-1 is either associated with significantly earlier relapse or worse patient overall survival [13].…”

Section: Introductionmentioning

confidence: 92%

Netrin-1 Expression Is an Independent Prognostic Factor for Poor Patient Survival in Brain Metastases

et al. 2014

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The multifunctional molecule netrin-1 is upregulated in various malignancies and has recently been presented as a major general player in tumorigenesis leading to tumor progression and maintenance in various animal models. However, there is still a lack of clinico-epidemiological data related to netrin-1 expression. Therefore, the aim of our study was to elucidate the association of netrin-1 expression and patient survival in brain metastases since those constitute one of the most limiting factors for patient prognosis. We investigated 104 brain metastases cases for netrin-1 expression using in-situ hybridization and immunohistochemistry with regard to clinical parameters such as patient survival and MRI data. Our data show that netrin-1 is strongly upregulated in most cancer subtypes. Univariate analyses revealed netrin-1 expression as a significant factor associated with poor patient survival in the total cohort of brain metastasis patients and in sub-entities such as non-small cell lung carcinomas. Interestingly, many cancer samples showed a strong nuclear netrin-1 signal which was recently linked to a truncated netrin-1 variant that enhances tumor growth. Nuclear netrin-1 expression was associated with poor patient survival in univariate as well as in multivariate analyses. Our data indicate both total and nuclear netrin-1 expression as prognostic factors in brain metastases patients in contrast to other prognostic markers in oncology such as patient age, number of brain metastases or Ki67 proliferation index. Therefore, nuclear netrin-1 expression constitutes one of the first reported molecular biomarkers for patient survival in brain metastases. Furthermore, netrin-1 may constitute a promising target for future anti-cancer treatment approaches in brain metastases.

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“…[14][15][16] There is also evidence showing that netrin-1 acts as a proangiogenic factor through Unc-5 Netrin Receptor B (UNC5B) and extracellular-signal-regulated kinase (ERK)-1/2-endothelial nitric oxide synthase (eNOS) mechanism to enhance tumor angiogenesis, thereby driving tumorigenesis. [14][15][16][17][18][19] Papanastasiou et al 20 have demonstrated that netrin-1 is strongly expressed in ovarian malignant tumors but not in nontumor tissues, suggesting that netrin-1 may represent a new biomarker for ovarian cancer, whereas how netrin-1 regulates the growth of ovarian cancer remains uncertain. In this study, we sought to investigate the role of SOX6 and netrin-1 in regulating the biological properties of ovarian cancer cells and the relationship between SOX6 and netrin-1 expression in the cells.…”

Section: Introductionmentioning

confidence: 99%

The role of Sox6 and Netrin-1 in ovarian cancer cell growth, invasiveness, and angiogenesis

Xiao

Guo

2017

Tumour Biol.

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SOX6 plays important roles in cell proliferation, differentiation, and cell fate determination. It has been confirmed that SOX6 is a tumor suppressor and downregulated in various cancers, including esophageal squamous cell carcinoma, hepatocellular carcinoma, and chronic myeloid leukemia. Netrin-1 is highly expressed in various human cancers and acts as an anti-apoptotic and proangiogenic factor to drive tumorigenesis. The role of SOX6 and netrin-1 in regulating the growth of ovarian tumor cells still remains unclear. Real-time polymerase chain reaction and western blot were used to determine the SOX6 messenger RNA and protein levels, respectively, in ovarian cancer cells and tumor tissues. Stable transfection of SOX6 was conducted to overexpress SOX6 in PA-1 and SW626 cells. Cell viability was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Invasion of ovarian cancer cells and migration of human umbilical vein endothelial cells were confirmed by Transwell assays. To overexpress netrin-1, ovarian cancer cells with SOX6 restoration was transduced with netrin-1 lentiviral particles. PA-1 xenografts in a nude mice model were used to conduct in vivo evaluation of the role of SOX6 and its relationship with netrin-1 in tumor growth and angiogenesis. In this study, we found significantly reduced SOX6 levels in PA-1, SW626, SK-OV-3, and CaoV-3 ovarian cancer cell lines and human tumor tissues in comparison with normal human ovarian epithelial cells or matched non-tumor tissues. SOX6 overexpression by stable transfection dramatically inhibited proliferation and invasion of PA-1 and SW626 cells. Also, conditioned medium from PA-1 and SW626 cells with SOX6 restoration exhibited reduced ability to induce human umbilical vein endothelial cells migration and tube formation compared with conditioned medium from the cells with transfection control. Furthermore, an inverse relationship between SOX6 and netrin-1 expression was observed in PA-1 and SW626 cells. Overexpression of netrin-1 in ovarian cancer cells with forced SOX6 expression remarkably abrogated the inhibitory effect of SOX6 on proliferation, invasion of the cells, and tumor xenograft growth and vascularity in vivo. Human umbilical vein endothelial cell migration and tube formation were enhanced in the conditioned medium from the ovarian cancer cells transduced with netrin-1 lentivirus particles. Our observations revealed that SOX6 is a tumor suppressor in ovarian cancer cells, and SOX6 exerts an inhibitory effect on the proliferation, invasion, and tumor cell-induced angiogenesis of ovarian cancer cells, whereas nerin-1 plays an opposite role and its expression is inversely correlated with SOX6. Moreover, our findings suggest a new role of SOX6 and netrin-1 for understanding the progression of ovarian cancer and have the potential for the development of new diagnosis and treatment strategies for ovarian cancer.

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Netrin-1 concentrations in patients with advanced gastric cancer and its relation with treatment

Abstract: Our results indicated that netrin-1 concentrations elevated in advanced gastric cancer compared to a healthy control group and netrin-1 concentrations decreased with chemotherapy.

Cited by 20 publications

References 23 publications

Aspirin‐induced histone acetylation in endothelial cells enhances synthesis of the secreted isoform of netrin‐1 thus inhibiting monocyte vascular infiltration

Aspirin‐induced histone acetylation in endothelial cells enhances synthesis of the secreted isoform of netrin‐1 thus inhibiting monocyte vascular infiltration

Netrin-1 Expression Is an Independent Prognostic Factor for Poor Patient Survival in Brain Metastases

The role of Sox6 and Netrin-1 in ovarian cancer cell growth, invasiveness, and angiogenesis

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