Winkles, J.A. The TWEAK-Fn14 cytokine-receptor axis: discovery, biology and therapeutic targeting. Nat. Rev. Drug Discov. 7, 411-425

Department of Surgery, Center for Vascular and Inflammatory Diseases, and the Marlene and Stewart Greenebaum Cancer Center, 800 West Baltimore Street, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
dressNature Reviews Drug Discovery (Impact Factor: 37.23). 06/2008; 7(5):411-25. DOI: 10.1038/nrd2488
Source: PubMed

ABSTRACT TWEAK is a multifunctional cytokine that controls many cellular activities including proliferation, migration, differentiation, apoptosis, angiogenesis and inflammation. TWEAK acts by binding to Fn14, a highly inducible cell-surface receptor that is linked to several intracellular signalling pathways, including the nuclear factor-kappaB (NF-kappaB) pathway. The TWEAK-Fn14 axis normally regulates various physiological processes, in particular it seems to play an important, beneficial role in tissue repair following acute injury. Furthermore, recent studies have indicated that TWEAK-Fn14 axis signalling may contribute to cancer, chronic autoimmune diseases and acute ischaemic stroke. This Review provides an overview of TWEAK-Fn14 axis biology and summarizes the available data supporting the proposal that both TWEAK and Fn14 should be considered as potential targets for the development of novel therapeutics.

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Available from: Jeffrey A Winkles, Jan 15, 2015
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    • "Tumor necrosis factor-like weak inducer of apoptosis (Tnfsf12, TWEAK) is a type II transmembrane glycoprotein of the TNF superfamily [1]. TWEAK induces, through its receptor fibroblast growth factorinducible 14 (Fn14), a high number of physiological and pathological processes depending on cell type and environment [1].TWEAK is broadly expressed in healthy and pathological vessels and changes on its expression are moderate [2]. However, Fn14 is expressed at very low levels under normal conditions but its expression is increased under a pathological scenario such as atherosclerosis [2]. "
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    ABSTRACT: Reduced soluble tumor necrosis factor-like weak inducer of apoptosis (sTWEAK) levels have been related with cardiovascular disease. However, there are no data on the relationship between sTWEAK and atherosclerotic burden in subjects with or without cardiovascular risk factors but free from clinical disease. We have analyzed the association between circulating sTWEAK levels and the presence of carotid and/or femoral atherosclerotic plaques in subjects without known vascular disease.
    Atherosclerosis 04/2015; 239(2). DOI:10.1016/j.atherosclerosis.2015.01.040 · 3.97 Impact Factor
    • "Possible issues contributing to this include: (i) adhesive interactions with nontarget structures, (ii) target(s) present on only a relatively small percentage of tumor cells or regions, (iii) target(s) not specific for invading cancer cells [14] [27], and (iv) target(s) changes in the context of treatment(s) and/or disease progression [28]. Fibroblast growth factor-inducible 14 (Fn14) is a member of the tumor necrosis factor receptor (TNFR) superfamily and is an emerging molecular target for GBM and other cancers [29] [30]. Importantly, Fn14 is minimally expressed in normal human brain but highly expressed in high-grade gliomas with more malignant and invasive characteristics [31]. "
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    ABSTRACT: A major limitation in the treatment of glioblastoma (GBM), the most common and deadly primary brain cancer, is delivery of therapeutics to invading tumor cells outside of the area that is safe for surgical removal. A promising way to target invading GBM cells is via drug-loaded nanoparticles that bind to fibroblast growth factor-inducible 14 (Fn14), thereby potentially improving efficacy and reducing toxicity. However, achieving broad particle distribution and nanoparticle targeting within the brain remains a significant challenge due to the adhesive extracellular matrix (ECM) and clearance mechanisms in the brain. In this work, we developed Fn14 monoclonal antibody-decorated nanoparticles that can efficiently penetrate brain tissue. We show these Fn14-targeted brain tissue penetrating nanoparticles are able to (i) selectively bind to recombinant Fn14 but not brain ECM proteins, (ii) associate with and be internalized by Fn14-positive GBM cells, and (iii) diffuse within brain tissue in a manner similar to non-targeted brain penetrating nanoparticles. In addition, when administered intracranially, Fn14-targeted nanoparticles showed improved tumor cell co-localization in mice bearing human GBM xenografts compared to non-targeted nanoparticles. Minimizing non-specific binding of targeted nanoparticles in the brain may greatly improve the access of particulate delivery systems to remote brain tumor cells and other brain targets. Copyright © 2014 Elsevier Ltd. All rights reserved.
    Biomaterials 02/2015; 42:42-51. DOI:10.1016/j.biomaterials.2014.11.054 · 8.31 Impact Factor
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    • "The 4.3-fold FN14 induction post run in tapered MHC IIa fibers aligns with our laboratory’s recent finding that robust FN14 expression after exercise is associated with isolated fast-twitch fiber size increases from resistance training [6], [9]. A member of the TNFα superfamily, FN14 is a cell-surface receptor found on a variety of tissues including skeletal muscle [28] and appears to signal through the diverse NF-Kβ pathway [28], [29]. While linked to atrophy in pathological conditions [30], FN14 also appears necessary for muscle proliferation, differentiation, and regeneration in mice and cell culture [31], [32]. "
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    ABSTRACT: This study evaluated gene expression changes in gastrocnemius slow-twitch myosin heavy chain I (MHC I) and fast-twitch (MHC IIa) muscle fibers of collegiate cross-country runners (n = 6, 20±1 y, VO2max = 70±1 ml•kg−1•min−1) during two distinct training phases. In a controlled environment, runners performed identical 8 kilometer runs (30:18±0:30 min:s, 89±1% HRmax) while in heavy training (~72 km/wk) and following a 3 wk taper. Training volume during the taper leading into peak competition was reduced ~50% which resulted in improved race times and greater cross-section and improved function of MHC IIa fibers. Single muscle fibers were isolated from pre and 4 hour post run biopsies in heavily trained and tapered states to examine the dynamic acute exercise response of the growth-related genes Fibroblast growth factor-inducible 14 (FN14), Myostatin (MSTN), Heat shock protein 72 (HSP72), Muscle ring-finger protein-1 (MURF1), Myogenic factor 6 (MRF4), and Insulin-like growth factor 1 (IGF1) via qPCR. FN14 increased 4.3-fold in MHC IIa fibers with exercise in the tapered state (P<0.05). MSTN was suppressed with exercise in both fiber types and training states (P<0.05) while MURF1 and HSP72 responded to running in MHC IIa and I fibers, respectively, regardless of training state (P<0.05). Robust induction of FN14 (previously shown to strongly correlate with hypertrophy) and greater overall transcriptional flexibility with exercise in the tapered state provides an initial molecular basis for fast-twitch muscle fiber performance gains previously observed after taper in competitive endurance athletes.
    PLoS ONE 09/2014; 9(9):e108547. DOI:10.1371/journal.pone.0108547 · 3.23 Impact Factor
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