Pigment Epithelium-derived Factor (PEDF) Promotes Tumor Cell Death by Inducing Macrophage Membrane Tumor Necrosis Factor-related Apoptosis-inducing Ligand (TRAIL)

Ho, Tzyy‐Chang; Chen, Show‐Li; Shih, Shou‐Chuan; Chang, Shing‐Jyh; Yang, Sung-Sen; Hsieh, Jui-Wen; Cheng, Huey-Chuan; Chen, Lee-Jen; Tsao, Yeou‐Ping

doi:10.1074/jbc.m111.266064

Cited by 35 publications

(39 citation statements)

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“…Some of these studies demonstrated the requirement for macrophages in T cell-dependent tumor rejection (11). Inoculation of TNF, PEDF, agonistic anti-CD40 mAb, CpG, or polyinosinic-polycytidylic acid into tumor-bearing mice stimulated tumor-infiltrating macrophages to kill cancer cells (12)(13)(14)(15)(16). These contrary observations may be due to the fact that macrophage functions are significantly affected by cytokines (17,18).…”

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confidence: 65%

“…Many studies indicated that tumor-associated macrophages are alternatively activated and promote cancer progression by accelerating the local invasion and metastasis of cancers (4)(5)(6)(7). In contrast, other studies revealed the anticancer activity of macrophages in mouse or rat models (8)(9)(10)(11)(12)(13)(14)(15)(16). Some of these studies demonstrated the requirement for macrophages in T cell-dependent tumor rejection (11).…”

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confidence: 96%

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Therapy of Peritoneally Disseminated Colon Cancer by TAP-Deficient Embryonic Stem Cell–Derived Macrophages in Allogeneic Recipients

Haga

Endo

Haruta

et al. 2014

The Journal of Immunology

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We established a method to generate a large quantity of myeloid lineage cells from mouse embryonic stem (ES) cells, termed ES cell–derived proliferating myeloid cell lines (ES-ML). ES-ML continuously proliferated in the presence of M-CSF and GM-CSF. ES-ML genetically modified to express an anti-HER2 (neu) mAb single-chain V region fragment reduced the number of cocultured mouse Colon-26 cancer cells expressing HER2. Stimulation of ES-ML with IFN-γ plus LPS or TNF resulted in almost complete killing of the Colon-26 cells by the ES-ML, and the cytotoxicity was mediated, in part, by NO produced by ES-ML. When ES-ML were injected into mice with i.p. established Colon-26 tumors, they efficiently infiltrated the tumor tissues. Injection of ES-ML with rIFN-γ and LPS inhibited cancer progression in the mouse peritoneal cavity. Coinjection of TNF-transfected or untransfected ES-ML with rIFN-γ inhibited cancer growth and resulted in prolonged survival of the treated mice. In this experiment, transporter associated with Ag processing (TAP)1-deficient ES-ML exhibited therapeutic activity in MHC-mismatched allogeneic recipient mice. Despite the proliferative capacity of ES-ML, malignancy never developed from the transferred ES-ML in the recipient mice. In summary, TAP-deficient ES-ML with anticancer properties exhibited a therapeutic effect in allogeneic recipients, suggesting the possible use of TAP-deficient human-induced pluripotent stem cell–derived proliferating myeloid cell lines in cancer therapy.

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confidence: 65%

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confidence: 96%

Therapy of Peritoneally Disseminated Colon Cancer by TAP-Deficient Embryonic Stem Cell–Derived Macrophages in Allogeneic Recipients

Haga

Endo

Haruta

et al. 2014

The Journal of Immunology

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“…[16][17][18][19][20] PEDF has an array of unique properties including neuroprotective, anti-angiogenic, antiinflammatory, anti-oxidative, and antitumorigenic activities. [21][22][23][24][25][26][27] PEDF is a multifaceted NTF that is active in a variety of ocular disorders including diabetic retinopathy and ischemic degeneration. 13,21,28,29 Although major sources of PEDF are choroid, ciliary body, and corneal epithelium, constitutive expression is also detected in RGC and photoreceptors.…”

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confidence: 99%

Pigment Epithelium-Derived Factor Is Retinal Ganglion Cell Neuroprotective and Axogenic After Optic Nerve Crush Injury

Vigneswara¹,

Berry²,

Logan³

et al. 2013

Invest. Ophthalmol. Vis. Sci.

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Citation: Vigneswara V, Berry M, Logan A, Ahmed Z. Pigment epithelium-derived factor is retinal ganglion cell neuroprotective and axogenic after optic nerve crush injury. Invest Ophthalmol Vis Sci. 2013;54: 262454: -263354: . DOI: 10.1167 PURPOSE. To investigate neuroprotective and axogenic properties of pigment epitheliumderived factor (PEDF) in retinal ganglion cells (RGC) in vitro and in vivo.METHODS. Adult rat retinal cultures were treated with combinations of PBS and PEDF with or without a cell permeable analogue of cAMP, and RGC survival and neurite lengths quantified. The optic nerves of anesthetised rats were also crushed intraorbitally to transect all RGC axons followed by intravitreal injections of either PBS, PEDF, or cAMPþPEDF every 7 days. RGC were back filled with FluoroGold to quantify RGC survival and longitudinal optic nerve sections were stained with GAP43 antibodies to detect regenerating RGC axons.RESULTS. An optimal dose of 2.5 3 10 À5 lg/lL, promoted 65% more RGC survival than controls in vitro, increasing by 4.4-and 5-fold the number of RGC with neurites and the mean neurite length, respectively. Addition of cAMP with or without PEDF did not potentiate RGC survival or the mean number of RGC with neurites, but enhanced RGC neurite length by 1.4-fold, compared with PEDF alone. After optic nerve crush (ONC), PEDF protected RGC from apoptosis and increased the numbers of regenerating RGC axons in the optic nerve by 4.6-and 3.4-fold, respectively when compared with controls. cAMP did not enhance PEDF-induced RGC neuroprotection, but potentiated its neuroregenerative effects by 2-to 3-fold, increasing the number of RGC axons regenerating at 500 and 1000 lm from the lesions site.CONCLUSIONS. This study is the first to demonstrate that PEDF enhances both RGC survival and axon regeneration in vitro and in vivo.Keywords: PEDF, retinal ganglion cells, neuroprotection, axon regeneration, optic nerve R etinal ganglion cells (RGC) rapidly die after axotomy, but are protected by combinatorial treatments with neurotrophic factors (NTF), including brain-derived NTF (BDNF), neurotrophin-3/4 (NT-3/4), ciliary neurotrophic factor (CNTF), glial cell line-derived neurotrophic (GDNF), and basic fibroblast growth factor (FGF2). 1-7 NTF combinations also activate intrinsic axon growth signalling pathways that initiate RGC axon regeneration.1-7 Pigment epithelium-derived factor (PEDF) is a 50 kDa NTF glycoprotein belonging to the serpin superfamily, that protects a wide range of central nervous system (CNS) neurons. [8][9][10][11][12][13][14][15] Although first isolated from fetal human retinal pigment (choroid) epithelial cells, like many other NTF, PEDF is expressed in a wide variety of tissues including brain, spinal cord, skeletal muscle, heart, endothelial cells, and osteoblasts. [16][17][18][19][20] PEDF has an array of unique properties including neuroprotective, anti-angiogenic, antiinflammatory, anti-oxidative, and antitumorigenic activities. [21][22][23][24][25][26][27] PEDF is a multifaceted NTF that ...

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“…PEDF belongs to the serine protease inhibitors (serpin) superfamily, as a noninhibitory member (Steele et al 1993), which is susceptible to proteolytic cleavage by matrix metalloproteinases (Notari et al 2005). A potent anti-angiogenic factor, PEDF induces apoptosis of endothelial cells, utilizing several distinct pathways (Chen et al 2006;Ho et al 2007Ho et al , 2011Volpert et al 2002). Furthermore, PEDF blocks migration of endothelial cells in response to a wide variety of pro-angiogenic agents, including vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) among others (Dawson et al 1999).…”

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confidence: 99%

Recombinant pigment epithelium-derived factor PEDF binds vascular endothelial growth factor receptors 1 and 2

Johnston

Francis

Knepper

2015

In Vitro Cell.Dev.Biol.-Animal

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Angiogenesis, or the formation of new blood vessels, is stimulated by angiogenic factors such as vascular endothelial growth factor (VEGF). Pigment epithelium-derived factor (PEDF) is a potent inhibitor of angiogenesis. To explore the mechanism by which PEDF acts, recombinant PEDF was expressed with a 6x-His tag (for purification) and a green fluorescent protein (GFP) tag. The PEDF fusion protein was confirmed to be active in inhibition of endothelial cell proliferation and migration. Direct binding of PEDF to both vascular endothelial growth factor receptor-1 (VEGFR-1) and VEGFR-2 was demonstrated in an in vitro assay similar to an enzyme-linked immunosorbent assay (ELISA). PEDF was shown by immune-confocal microscopy to be localized within treated endothelial cells. When VEGF-stimulated endothelial cells were incubated with PEDF the VEGF receptors showed intracellular localization. These data suggest that the interaction between PEDF and VEGFR-1 or VEGFR-2 may be a possible mechanism for inhibiting angiogenesis. PEDF may be binding to the VEGF receptors to promote their internalization and/or degradation to limit VEGF responses in treated cells.

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Pigment Epithelium-derived Factor (PEDF) Promotes Tumor Cell Death by Inducing Macrophage Membrane Tumor Necrosis Factor-related Apoptosis-inducing Ligand (TRAIL)

Cited by 35 publications

References 54 publications

Therapy of Peritoneally Disseminated Colon Cancer by TAP-Deficient Embryonic Stem Cell–Derived Macrophages in Allogeneic Recipients

Therapy of Peritoneally Disseminated Colon Cancer by TAP-Deficient Embryonic Stem Cell–Derived Macrophages in Allogeneic Recipients

Pigment Epithelium-Derived Factor Is Retinal Ganglion Cell Neuroprotective and Axogenic After Optic Nerve Crush Injury

Recombinant pigment epithelium-derived factor PEDF binds vascular endothelial growth factor receptors 1 and 2

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