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Increased Levels of NF-kB-Dependent Markers in Cancer-Associated Deep Venous Thrombosis.

Malaponte G, Signorelli SS, Bevelacqua V, Polesel J, Taborelli M, Guarneri C, Fenga C, Umezawa K, Libra M - PLoS ONE (2015)

Bottom Line: However, their combined role in cancer-associated deep vein thrombosis (DVT) and the molecular mechanisms, involved in its pathophysiology, needs further investigations.Accordingly, significantly higher NF-kB activity was observed in cancer patients DVT+ than DVT-.NF-kB inhibition was associated with decreased levels of all molecules in both cancer DVT+ and DVT-.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical and Biotechnological Sciences, Section of General & Clinical Pathology and Oncology, University of Catania, Catania, Italy.

ABSTRACT
Several studies highlight the role of inflammatory markers in thrombosis as well as in cancer. However, their combined role in cancer-associated deep vein thrombosis (DVT) and the molecular mechanisms, involved in its pathophysiology, needs further investigations. In the present study, C-reactive protein, interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1β), matrix metalloproteases-9 (MMP-9), vascular endothelial growth factor (VEGF), tissue factor (TF), fibrinogen and soluble P-selectin, were analyzed in plasma and in monocyte samples from 385 cancer patients, of whom 64 were concomitantly affected by DVT (+). All these markers were higher in cancer patients DVT+ than in those DVT-. Accordingly, significantly higher NF-kB activity was observed in cancer patients DVT+ than DVT-. Significant correlation between data obtained in plasma and monocyte samples was observed. NF-kB inhibition was associated with decreased levels of all molecules in both cancer DVT+ and DVT-. To further demonstrate the involvement of NF-kB activation by the above mentioned molecules, we treated monocyte derived from healthy donors with a pool of sera from cancer patients with and without DVT. These set of experiments further suggest the significant role played by some molecules, regulated by NF-kB, and detected in cancer patients with DVT. Our data support the notion that NF-kB may be considered as a therapeutic target for cancer patients, especially those complicated by DVT. Treatment with NF-kB inhibitors may represent a possible strategy to prevent or reduce the risk of DVT in cancer patients.

No MeSH data available.


Related in: MedlinePlus

Effect of dehydroxymethylepoxyquinomicin (DHMEQ) on lipopolysaccharide (LPS)-induced nuclear factor (NF)–kB p65 activation in monocytes from cancer patients with and without DVT.Nuclear extracts were prepared from monocytes, pretreated and not with DHMEQ (10 μg/mL) for 2 h and after which stimulated with 100 ng/ml LPS for 24 hour, using a Nuclear Extract Kit. The stimulation of monocytes with LPS at 100 ng/mL induce un significant increase of the nuclear NF-kB p65 protein level in all groups or cancer patients DVT+, DVT- and in healthy controls, compared to unstimulated cells, (P<0.0001). NF-kB p65 subunit was significantly higher in cancer patients DVT+ than in those DVT- (P< 0.0001) (t-test). DVT, Deep Vein thrombosis.
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pone.0132496.g003: Effect of dehydroxymethylepoxyquinomicin (DHMEQ) on lipopolysaccharide (LPS)-induced nuclear factor (NF)–kB p65 activation in monocytes from cancer patients with and without DVT.Nuclear extracts were prepared from monocytes, pretreated and not with DHMEQ (10 μg/mL) for 2 h and after which stimulated with 100 ng/ml LPS for 24 hour, using a Nuclear Extract Kit. The stimulation of monocytes with LPS at 100 ng/mL induce un significant increase of the nuclear NF-kB p65 protein level in all groups or cancer patients DVT+, DVT- and in healthy controls, compared to unstimulated cells, (P<0.0001). NF-kB p65 subunit was significantly higher in cancer patients DVT+ than in those DVT- (P< 0.0001) (t-test). DVT, Deep Vein thrombosis.

Mentions: As shown in Fig 3, treatment of monocytes with LPS at 100 ng/mL strongly activated NF-kB p65 of 46%, 73% and 35% over the basal value compared to unstimulated cells in cancer patients DVT+, DVT- and in healthy controls, respectively (p<0.0001). Preincubation with DHMEQ, prior to LPS stimulation, strongly decreased NF-kB p65 subunit activity of 4.5-fold, 3-fold and 3.2-fold in cancer DVT+ and DVT- and in healthy controls (p<0,0001), respectively, compared with LPS alone. To reinforce our findings on NF-kBp65 down-regulation by DHMEQ in LPS-activated monocytes, the amount of NF-kB p65 subunit activity in nuclear extracts from the same experiments were subsequently measured by ELISA. As expected, treatment with DHMEQ in LPS stimulated monocyte induced the decrease of NF-kB activity among the three groups analyzed (Fig 3).


Increased Levels of NF-kB-Dependent Markers in Cancer-Associated Deep Venous Thrombosis.

Malaponte G, Signorelli SS, Bevelacqua V, Polesel J, Taborelli M, Guarneri C, Fenga C, Umezawa K, Libra M - PLoS ONE (2015)

Effect of dehydroxymethylepoxyquinomicin (DHMEQ) on lipopolysaccharide (LPS)-induced nuclear factor (NF)–kB p65 activation in monocytes from cancer patients with and without DVT.Nuclear extracts were prepared from monocytes, pretreated and not with DHMEQ (10 μg/mL) for 2 h and after which stimulated with 100 ng/ml LPS for 24 hour, using a Nuclear Extract Kit. The stimulation of monocytes with LPS at 100 ng/mL induce un significant increase of the nuclear NF-kB p65 protein level in all groups or cancer patients DVT+, DVT- and in healthy controls, compared to unstimulated cells, (P<0.0001). NF-kB p65 subunit was significantly higher in cancer patients DVT+ than in those DVT- (P< 0.0001) (t-test). DVT, Deep Vein thrombosis.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4507873&req=5

pone.0132496.g003: Effect of dehydroxymethylepoxyquinomicin (DHMEQ) on lipopolysaccharide (LPS)-induced nuclear factor (NF)–kB p65 activation in monocytes from cancer patients with and without DVT.Nuclear extracts were prepared from monocytes, pretreated and not with DHMEQ (10 μg/mL) for 2 h and after which stimulated with 100 ng/ml LPS for 24 hour, using a Nuclear Extract Kit. The stimulation of monocytes with LPS at 100 ng/mL induce un significant increase of the nuclear NF-kB p65 protein level in all groups or cancer patients DVT+, DVT- and in healthy controls, compared to unstimulated cells, (P<0.0001). NF-kB p65 subunit was significantly higher in cancer patients DVT+ than in those DVT- (P< 0.0001) (t-test). DVT, Deep Vein thrombosis.
Mentions: As shown in Fig 3, treatment of monocytes with LPS at 100 ng/mL strongly activated NF-kB p65 of 46%, 73% and 35% over the basal value compared to unstimulated cells in cancer patients DVT+, DVT- and in healthy controls, respectively (p<0.0001). Preincubation with DHMEQ, prior to LPS stimulation, strongly decreased NF-kB p65 subunit activity of 4.5-fold, 3-fold and 3.2-fold in cancer DVT+ and DVT- and in healthy controls (p<0,0001), respectively, compared with LPS alone. To reinforce our findings on NF-kBp65 down-regulation by DHMEQ in LPS-activated monocytes, the amount of NF-kB p65 subunit activity in nuclear extracts from the same experiments were subsequently measured by ELISA. As expected, treatment with DHMEQ in LPS stimulated monocyte induced the decrease of NF-kB activity among the three groups analyzed (Fig 3).

Bottom Line: However, their combined role in cancer-associated deep vein thrombosis (DVT) and the molecular mechanisms, involved in its pathophysiology, needs further investigations.Accordingly, significantly higher NF-kB activity was observed in cancer patients DVT+ than DVT-.NF-kB inhibition was associated with decreased levels of all molecules in both cancer DVT+ and DVT-.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical and Biotechnological Sciences, Section of General & Clinical Pathology and Oncology, University of Catania, Catania, Italy.

ABSTRACT
Several studies highlight the role of inflammatory markers in thrombosis as well as in cancer. However, their combined role in cancer-associated deep vein thrombosis (DVT) and the molecular mechanisms, involved in its pathophysiology, needs further investigations. In the present study, C-reactive protein, interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1β), matrix metalloproteases-9 (MMP-9), vascular endothelial growth factor (VEGF), tissue factor (TF), fibrinogen and soluble P-selectin, were analyzed in plasma and in monocyte samples from 385 cancer patients, of whom 64 were concomitantly affected by DVT (+). All these markers were higher in cancer patients DVT+ than in those DVT-. Accordingly, significantly higher NF-kB activity was observed in cancer patients DVT+ than DVT-. Significant correlation between data obtained in plasma and monocyte samples was observed. NF-kB inhibition was associated with decreased levels of all molecules in both cancer DVT+ and DVT-. To further demonstrate the involvement of NF-kB activation by the above mentioned molecules, we treated monocyte derived from healthy donors with a pool of sera from cancer patients with and without DVT. These set of experiments further suggest the significant role played by some molecules, regulated by NF-kB, and detected in cancer patients with DVT. Our data support the notion that NF-kB may be considered as a therapeutic target for cancer patients, especially those complicated by DVT. Treatment with NF-kB inhibitors may represent a possible strategy to prevent or reduce the risk of DVT in cancer patients.

No MeSH data available.


Related in: MedlinePlus