Transforming growth factor (TGF)-β expression and activation mechanisms as potential targets for anti-tumor therapy and tumor imaging

Arjaans, Marlous; Munnink, Thijs H. Oude; Timmer‐Bosscha, Hetty; Reiß, Michael; Walenkamp, Annemiek; Hooge, Marjolijn N. Lub-de; Vries, Elisabeth G.E. de; Schröder, Carolina P.

doi:10.1016/j.pharmthera.2012.05.001

Cited by 36 publications

(27 citation statements)

References 84 publications

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“…After processing, TGF-β 1 remains noncovalently bound to latency-associated peptide (LAP), forming small latent TGF-β 1 (LTGF-β 1 ). In the cytoplasm, the small LTGF-β 1 binds to latent TGF-β binding protein with a disulfide bond, forming large LTGF-β 1 [1,2]. TGF-β 1 is secreted from cells as small LTGF-β 1 , or more commonly as large LTGF-β 1 [2].…”

Section: Introductionmentioning

confidence: 99%

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Heparin Inhibits Activation of Latent Transforming Growth Factor-β<sub>1</sub>

Lee

2013

Pharmacology

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Aim: Besides acting as an anticoagulant, heparin has antifibrotic effects. Transforming growth factor-β₁ (TGF-β₁) is secreted from cells as latent TGF-β₁ (LTGF-β₁). LTGF-β₁ consists of TGF-β₁ and latency-associated peptide (LAP). To be biologically active, TGF-β₁ has to be released from LAP. Heparin binds to LAP as well as TGF-β₁. This study was performed to explore the biological effect of the interaction of heparin with LTGF-β₁. Materials and Methods: TGF-β₁ was measured by ELISA. Furin-like proprotein convertase activity was assayed using the fluorogenic substrate, Pyr-Arg-Thr-Lys-Arg-AMC. Results: Heparin did not interfere with the receptor binding of TGF-β₁, but inhibited furin-like proprotein convertase-mediated activation of platelet LTGF-β₁. This was not by inhibition of the enzyme because heparin did not inhibit the activity of furin-like proprotein convertase. In addition, heparin inhibited acid activations of recombinant small LTGF-β₁, platelet LTGF-β₁ and LTGF-β₁s secreted in the supernatant of cultured cells. Low-molecular-weight heparins, including dalteparin, enoxaparin and nadroparin, also had inhibitory effects on furin-like proprotein convertase-mediated or acid activation of platelet LTGF-β₁. Conclusion: The findings suggest that heparin renders LTGF-β₁ resistant to activation, possibly by binding simultaneously to TGF-β₁ and LAP. Inhibition of LTGF-β₁ activation by heparin may in part account for its antifibrotic effects.

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Section: Introductionmentioning

confidence: 99%

“…LTGF-β 1 itself does not bind to TGF-β receptor and thus has no biological activity of TGF-β 1 . To be biologically active, TGF-β 1 has to be cleaved and released from LAP of the latent complex [1]. After that, it can bind to TGF-β receptor type II (TGF-βRII) on the cell surface, and subsequently induces the biological responses [1].…”

Section: Introductionmentioning

confidence: 99%

Heparin Inhibits Activation of Latent Transforming Growth Factor-β<sub>1</sub>

Lee

2013

Pharmacology

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“…In addition, progression-free survival (PFS) and overall survival are decreased in glioma patients with high levels of phosphorylated SMAD2 (p-SMAD2), the substrate of TGF-b receptor I, compared with glioma patients with low levels of p-SMAD2 (7). These features make TGF-b a promising target molecule for therapeutic approaches in recurrent glioma; therefore, several TGF-b-inhibitors are under investigation in this setting (8).…”

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confidence: 99%

TGF-β Antibody Uptake in Recurrent High-Grade Glioma Imaged with ⁸⁹Zr-Fresolimumab PET

et al. 2015

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Transforming growth factor-b (TGF-b) signaling is involved in glioma development. The monoclonal antibody fresolimumab (GC1008) can neutralize all mammalian isoforms of TGF-b, and tumor uptake can be visualized and quantified with 89 Zr-fresolimumab PET in mice. The aim of this study was to investigate the fresolimumab uptake in recurrent high-grade gliomas using 89 Zr-fresolimumab PET and to assess treatment outcome in patients with recurrent high-grade glioma treated with fresolimumab. Methods: Patients with recurrent glioma were eligible. After intravenous administration of 37 MBq (5 mg) of 89 Zr-fresolimumab, PET scans were acquired on day 2 or day 4 after tracer injection. Thereafter, patients were treated with 5 mg of fresolimumab per kilogram intravenously every 3 wk. 89 Zr-fresolimumab tumor uptake was quantified as maximum standardized uptake value (SUV max ). MR imaging for response evaluation was performed after 3 infusions or as clinically indicated. Results: Twelve patients with recurrent high-grade glioma were included: 10 glioblastomas, 1 anaplastic oligodendroglioma, and 1 anaplastic astrocytoma. All patients underwent 89 Zr-fresolimumab PET 4 d after injection. In 4 patients, an additional PET scan was obtained on day 2 after injection. SUV max on day 4 in tumor lesions was 4.6 (range, 1.5-13.9) versus a median SUV mean of 0.3 (range, 0.2-0.5) in normal brain tissue. All patients showed clinical or radiologic progression after 1-3 infusions of fresolimumab. Median progression-free survival was 61 d (range, 25-80 d), and median overall survival was 106 d (range, 37-417 d). Conclusion: 89 Zr-fresolimumab penetrated recurrent high-grade gliomas very well but did not result in clinical benefit.

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“…The TGF-β family consists of three members, TGF-β1, TGF-β2 and TGF-β3 in mammals (Arjaans et al, 2012) TGF-βs are secreted with a dimeric Latency-Associated Peptide (LAP) in an inactive form called Small Latent Complex (SLC) and dissociation from LAP releases the approximately 25 kDa mature polypeptides (Hinck, 2012). Latent TGF-β Binding Proteins (LTBPs) are a family of fibrillin-like molecules that are covalently linked to SLC.…”

Section: Transforming Growth Factor-β (Tgf-β)mentioning

confidence: 99%

Progress in Relevant Growth Factors Promoting the Growth of Hair Follicle

Valerie¹

2012

American Journal of Animal and Veterinary Sciences

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Abstract:Hair is a protective appendage on the body that is considered accessory structure of the integument. Hair follicle development takes place during fetal skin development and relies on tightly regulated ectodermal-mesodermal interactions. The morphological changes of the hair cycle have been very clear that hair morphogenesis and epidermal development are orchestrated by an array of growth factors. In this review, we summarize the major growth factors involved in promoting growth of hair follicles.

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Transforming growth factor (TGF)-β expression and activation mechanisms as potential targets for anti-tumor therapy and tumor imaging

Cited by 36 publications

References 84 publications

Heparin Inhibits Activation of Latent Transforming Growth Factor-β<sub>1</sub>

Heparin Inhibits Activation of Latent Transforming Growth Factor-β<sub>1</sub>

TGF-β Antibody Uptake in Recurrent High-Grade Glioma Imaged with ⁸⁹Zr-Fresolimumab PET

Progress in Relevant Growth Factors Promoting the Growth of Hair Follicle

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Transforming growth factor (TGF)-β expression and activation mechanisms as potential targets for anti-tumor therapy and tumor imaging

Cited by 36 publications

References 84 publications

Heparin Inhibits Activation of Latent Transforming Growth Factor-β<sub>1</sub>

Heparin Inhibits Activation of Latent Transforming Growth Factor-β<sub>1</sub>

TGF-β Antibody Uptake in Recurrent High-Grade Glioma Imaged with 89Zr-Fresolimumab PET

Progress in Relevant Growth Factors Promoting the Growth of Hair Follicle

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Product

Resources

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TGF-β Antibody Uptake in Recurrent High-Grade Glioma Imaged with ⁸⁹Zr-Fresolimumab PET