Plasminogen Activators and Plasminogen Activator Inhibitor before and after Surgery in Patients with and without Gastric Malignancy

Rahr, Hans B; Sørensen, Jesper Roed; Larsen, Julie Brogaard; Jensen, Frank Svendsen; C, Bredahl

doi:10.1159/000217168

Cited by 4 publications

(3 citation statements)

References 12 publications

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“…TGF-␤1 released from platelets during trauma or surgery might also contribute to the transient increases in plasma levels of PAI-1 that occur after these phenomena if the released latent TGF-␤1 becomes activated intravascularly and systemically activates endothelial cells. [41][42][43][44][45][46][47] This would provide a valuable homeostatic link between platelet activation to arrest hemorrhage and transient inhibition of fibrinolysis to allow the early unopposed deposition of fibrin to secure hemostasis. In addition, the ability of shear force to activate latent TGF-␤1 makes TGF-␤1 a potential shear sensor in addition to being a cellular effector.…”

Section: Discussionmentioning

confidence: 99%

In vitro and in vivo evidence for shear-induced activation of latent transforming growth factor-β1

Ahamed

Burg

Yoshinaga

et al. 2008

Blood

136

163

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Transforming growth factor-␤1 (TGF-␤1) has potent physiologic and pathologic effects on a variety of cell types at subnanomolar concentrations. Platelets contain 40 times as much TGF-␤1 as other cells and secrete it as an inactive (latent) form in complex with latency-associated peptide (LAP), which is disulfide bonded via Cys33 to latent TGF-␤ binding protein 1 (LTBP-1). Little is known about how latent TGF-␤1 becomes activated in vivo.Here we show that TGF-␤1 released from platelets or fibroblasts undergoes dramatic activation when subjected to stirring or shear forces, providing a potential mechanism for physiologic control. Thioldisulfide exchange appears to contribute to the process based on the effects of thiol-reactive reagents and differences in thiol labeling of TGF-␤1 before and after stirring or shear. Activation required the presence of LTBP, as TGF-␤1 contained in complex with only LAP could not be activated by stirring when studied as either a recombinant purified protein complex or in the platelet releasates or sera of mice engineered to contain an LAP C33S mutation. Release IntroductionTransforming growth factor-␤1 (TGF-␤1) has potent physiologic and pathologic effects on a variety of cell types at subnanomolar concentrations, including cells of the immune and hematopoietic systems, as well as malignant cells and fibroblasts, 1 with the latter responding with increased collagen production leading to tissue fibrosis. 2 Nearly all cellular TGF-␤1 exists, however, in a biologically inactive (latent) form in a noncovalent complex with the remaining portion of its precursor molecule, latency-associated peptide (LAP), which is disulfide bonded to a latent TGF-␤ binding protein 3,or 4), forming the large latent complex (LLC). 3 Although much is known about the signaling mechanisms and downstream effects of TGF-␤1, 4 and several latent TGF-␤1 activating mechanisms have been identified in vitro (reviewed in Annes et al 3 ), little is known about the physiologic mechanisms that control latent TGF-␤1 activation in vivo. Recent data support activation of LLC TGF-␤1 via a traction mechanism, 3,[5][6][7][8][9][10][11] with LAP binding to integrins ␣V␤5, ␣V␤6, and ␣V␤8, and LTBP-1 binding to extracellular matrix.Blood platelets are a rich source of TGF-␤1, containing 40 to 100 times as much as other cells, 12 and releasing it when activated by a variety of agents, including thrombin, which is produced during blood clotting. [13][14][15][16][17][18][19] Virtually all of the TGF-␤1 released from platelets is in the LLC. 3,16 Because platelet latent TGF-␤1 is released into the circulation, and because traction on the molecule has been proposed as a mechanism of latent TGF-␤1 activation, 5,6 we hypothesized that intravascular shear force may serve as an analog of traction mediated by cellular contraction and contribute to the activation of latent TGF-␤1 released from platelets. We therefore tested this hypothesis by both in vitro and in vivo experiments. Methods Antibodies and reagentsAnti-TGF-␤1 (polyclonal chi...

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Section: Discussionmentioning

confidence: 99%

In vitro and in vivo evidence for shear-induced activation of latent transforming growth factor-β1

Ahamed

Burg

Yoshinaga

et al. 2008

Blood

136

163

View full text Add to dashboard Cite

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“…Several experimental findings also demonstrated that the uPA-uPAR system plays a crucial role in invasion and metastasis of prostate cancer cells both in vitro and in vivo [9][10][11][12]. Furthermore, recent studies revealed that serum levels of uPA and uPAR appear to be indicative of malignancy in gastric and ovarian cancer [13][14][15]. Therefore, in the present study, serum levels of uPA and uPAR were examined in healthy controls, and in BPH and prostate cancer patients, and an investigation of whether they could be used as predictors of disease progression and prognosis in prostate cancer patients was conducted.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, elevated levels of uPA and uPAR in various body fluids of cancer patients, such as sera, ascites, and pleural effusions, were reported [13][14][15]. However, there has been no report regarding serum levels of uPA and uPAR in human prostate cancer patients.…”

Section: Introductionmentioning

confidence: 99%

Elevation of serum levels of urokinase-type plasminogen activator and its receptor is associated with disease progression and prognosis in patients with prostate cancer

et al. 1999

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BACKGROUND Several investigators have revealed that urokinase‐type plasminogen activator (uPA) and its receptor (uPAR) are overexpressed in serum as well as in tumor tissues in patients with various types of cancer. In this study, we examined whether the serum levels of uPA and uPAR could be used as predictors of the progression and prognosis of prostate cancer. METHODS Serum levels of uPA and uPAR in 54 healthy controls, 62 patients with benign prostatic hypertrophy (BPH), and 72 patients with prostate cancer were measured by a sandwich enzyme immunoassay. RESULTS The mean serum levels of uPA and uPAR in patients with prostate cancer were significantly higher than those in healthy controls and patients with BPH. Furthermore, the serum uPA and uPAR levels in prostate cancer patients with metastasis were significantly elevated compared with those in patients without metastasis. Among patients who underwent radical prostatectomy, the serum levels of uPA and uPAR in patients with pathologically organ‐confined disease were significantly lower than in those with advanced disease. The overall survival rate of prostate cancer patients with elevated serum levels of either uPA or uPAR, or of both, was significantly lower than that of patients with normal serum levels of uPA and uPAR. CONCLUSIONS The results of this study indicate that the elevation of serum levels of either uPA or uPAR, or of both, could be used as new predictors of progression and prognosis in patients with prostate cancer. Prostate 39:123–129, 1999. © 1999 Wiley‐Liss, Inc.

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The potential role of antivascular therapy in the adjuvant and neoadjuvant treatment of cancer

Los

Voest

2001

Seminars in Oncology

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Plasminogen Activators and Plasminogen Activator Inhibitor before and after Surgery in Patients with and without Gastric Malignancy

Cited by 4 publications

References 12 publications

In vitro and in vivo evidence for shear-induced activation of latent transforming growth factor-β1

In vitro and in vivo evidence for shear-induced activation of latent transforming growth factor-β1

Elevation of serum levels of urokinase-type plasminogen activator and its receptor is associated with disease progression and prognosis in patients with prostate cancer

The potential role of antivascular therapy in the adjuvant and neoadjuvant treatment of cancer

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