Platelets possess functional TGF-β receptors and Smad2 protein

Lev, Paola Roxana; Salim, Juan P.; Marta, Rosana Fernanda; Osorio, María José Mela; Goette, Nora Paula; Molinas, Felisa C.

doi:10.1080/09537100600800743

Cited by 26 publications

(17 citation statements)

References 33 publications

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“…The cascade of TGF-β/Smad2 and Snail related to EMT was investigated and similar to what was observed in N-cadherin, this cascade was significantly detected in the presence of the highest PRP concentration, and prominently detected in luminal A cells adhered to the network of fibrin bundles (Figure 4C). This cross-talk between the luminal A epithelial cells and PRP-fibrin bundles showed Smad2 expression in human platelets [37]. It is important to note that luminal A cells changed their adhesion site only when exposed to the 7.5% PRP supplementation, contrary to what was observed in the epithelial cells from luminal B and HER2+ tumors.…”

Section: Resultsmentioning

confidence: 99%

Interface between breast cancer cells and the tumor microenvironment using platelet-rich plasma to promote tumor angiogenesis - influence of platelets and fibrin bundles on the behavior of breast tumor cells

et al. 2017

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Cancer progression is associated with an evolving tissue interface of direct epithelial-tumor microenvironment interactions. In biopsies of human breast tumors, extensive alterations in molecular pathways are correlated with cancer staging on both sides of the tumor-stroma interface. These interactions provide a pivotal paracrine signaling to induce malignant phenotype transition, the epithelial-mesenchymal transition (EMT). We explored how the direct contact between platelets-fibrin bundles primes metastasis using platelet-rich plasma (PRP) as a source of growth factors and mimics the provisional fibrin matrix between actively growing breast cancer cells and the tumor stroma. We have demonstrated PRP functions, modulating cell proliferation that is tumor-subtype and cancer cell-type-specific. Epithelial and stromal primary cells were prepared from breast cancer biopsies from 21 women with different cancer subtypes. Cells supplemented with PRP were immunoblotted with anti-phospho and total Src-Tyr-416, FAK-Try-925, E-cadherin, N-cadherin, TGF-β, Smad2, and Snail monoclonal antibodies. Breast tumor cells from luminal B and HER2 subtypes showed the most malignant profiles and the expression of thrombin and other classes of proteases at levels that were detectable through FRET peptide libraries. The angiogenesis process was investigated in the interface obtained between platelet-fibrin-breast tumor cells co-cultured with HUVEC cells. Luminal B and HER2 cells showed robust endothelial cell capillary-like tubes ex vivo. The studied interface contributes to the attachment of endothelial cells, provides a source of growth factors, and is a solid substrate. Thus, replacement of FBS supplementation with PRP supplementation represents an efficient and simple approach for mimicking the real multifactorial tumor microenvironment.

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Section: Resultsmentioning

confidence: 99%

Interface between breast cancer cells and the tumor microenvironment using platelet-rich plasma to promote tumor angiogenesis - influence of platelets and fibrin bundles on the behavior of breast tumor cells

et al. 2017

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“…The specific contribution of TGF-β to thrombus formation however, is not thoroughly elucidated. TGF-β by itself does not induce platelet aggregation [32,34], but seems to have a slightly activating effect when used in combination with different platelet agonists, such as collagen, U46619, ADP and SFLLRNP [34,35]. As Cuende et al showed that inhibitory anti-GARP antibodies can block the release of active TGF-β on Treg, GARP may also be involved in the gradual release of active TGF-β on platelets and endothelium [11].…”

Section: Discussionmentioning

confidence: 99%

The role of platelet and endothelial GARP in thrombosis and hemostasis

et al. 2017

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BackgroundGlycoprotein-A Repetitions Predominant protein (GARP or LRRC32) is present on among others human platelets and endothelial cells. Evidence for its involvement in thrombus formation was suggested by full knockout of GARP in zebrafish.ObjectivesTo evaluate the role of GARP in platelet physiology and in thrombus formation using platelet and endothelial conditional GARP knock out mice.MethodsPlatelet and endothelial specific GARP knockout mice were generated using the Cre-loxP recombination system. The function of platelets without GARP was measured by flow cytometry, spreading analysis and aggregometry using PAR4-activating peptide and collagen related peptide. Additionally, clot retraction and collagen-induced platelet adhesion and aggregation under flow were analyzed. Finally, in vivo tail bleeding time, occlusion time of the mesenteric and carotid artery after FeCl3-induced thrombosis were determined in platelet and endothelial specific GARP knock out mice.ResultsPlatelet specific GARP knockout mice had normal surface GPIb, GPVI and integrin αIIb glycoprotein expression. Although GARP expression was increased upon platelet activation, platelets without GARP displayed normal agonist induced activation, spreading on fibrinogen and aggregation responses. Furthermore, absence of GARP on platelets did not influence clot retraction and had no impact on thrombus formation on collagen-coated surfaces under flow. In line with this, neither the tail bleeding time nor the occlusion time in the carotid- and mesenteric artery after FeCl3-induced thrombus formation in platelet or endothelial specific GARP knock out mice were affected.ConclusionsEvidence is provided that platelet and endothelial GARP are not important in hemostasis and thrombosis in mice.

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“…Increased sEng levels observed in PE women can impair TGF-β1 signaling in the vasculature by reducing the amount of TGF-β1 available to bind to its cell membrane receptors [7]. Moreover, platelet activation is a common feature in PE and activated platelets are the main sources of TGF-β1 in the circulation [37]. Thus, TGF-β1 secreted by activated platelets could play a compensatory role in preserving endothelial function in PE [23].…”

Section: Discussionmentioning

confidence: 99%

Soluble Endoglin, Transforming Growth Factor-Beta 1 and Soluble Tumor Necrosis Factor Alpha Receptors in Different Clinical Manifestations of Preeclampsia

Perucci¹,

Gomes

Freitas³

et al. 2014

PLoS ONE

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BackgroundDespite intensive research, the etiopathogenesis of preeclampsia (PE) remains uncertain. Inflammatory and angiogenic factors are thought to play considerable roles in this disease. The objective of this study was to investigate the association between soluble endoglin (sEng), transforming growth factor beta-1 (TGF-β1) and tumor necrosis factor alpha soluble receptors (sTNF-Rs) and the clinical manifestations of PE.MethodsPlasma levels of sEng, TGF-β1 and sTNF-Rs were determined by ELISA in 23 non-pregnant, 21 normotensive pregnant and 43 PE women. PE women were stratified into subgroups according to the severity [mild (n = 12) and severe (n = 31)] and onset-time of the disease [early (n = 19) and late (n = 24)].ResultsPregnancy was associated with higher levels of sEng, sTNF-R1 and sTNF-R2 than the non-pregnant state. Moreover, PE women had higher levels of sEng and sTNF-R1 than normotensive pregnant women. No difference was found in TGF-β1 levels, comparing the three study groups. Late PE had higher levels of sTNF-R1 and sTNF-R2 than early PE. No significant differences were found in sEng and TGF-β1 comparing early and late PE. sEng levels were higher in severe PE than in mild PE and no difference was found for TGF-β1, sTNF-R1 and sTNF-R2 levels. There was a positive correlation among sEng, TNF-R1 and sTNF-2 levels. Logistic regression analysis revealed that primiparity and sEng levels are independently associated with the development of PE. Furthermore, sEng levels are independently associated with the disease severity.ConclusionsThese results suggest that pregnancy is a condition associated with higher levels of anti-angiogenic and pro-inflammatory factors than the non-pregnant state and that PE is associated with an imbalance of these factors in the maternal circulation.

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Platelets possess functional TGF-β receptors and Smad2 protein

Cited by 26 publications

References 33 publications

Interface between breast cancer cells and the tumor microenvironment using platelet-rich plasma to promote tumor angiogenesis - influence of platelets and fibrin bundles on the behavior of breast tumor cells

Interface between breast cancer cells and the tumor microenvironment using platelet-rich plasma to promote tumor angiogenesis - influence of platelets and fibrin bundles on the behavior of breast tumor cells

The role of platelet and endothelial GARP in thrombosis and hemostasis

Soluble Endoglin, Transforming Growth Factor-Beta 1 and Soluble Tumor Necrosis Factor Alpha Receptors in Different Clinical Manifestations of Preeclampsia

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