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.
Nature Reviews Drug Discovery (Impact Factor: 41.91). 06/2008; 7(5):411-25. DOI: 10.1038/nrd2488
Source: PubMed


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
    • "Thus, targeting Fn14 on tumors presents a promising means for treatment of cancer cachexia. The finding that Fn14 is not only involved in wound healing (Winkles, 2008) but also causative of cancer cachexia is consistent with the concept that tumors resemble wounds that do not heal (Dvorak, 1986). We had specifically chosen antibodies to Fn14 that could antagonize the action of TWEAK, in line with the hypothesis that Fn14-dependent cachexia is caused by an activation of signaling through Fn14. "
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    ABSTRACT: The cytokine TWEAK and its cognate receptor Fn14 are members of the TNF/TNFR superfamily and are upregulated in tumors. We found that Fn14, when expressed in tumors, causes cachexia and that anti- bodies against Fn14 dramatically extended lifespan by inhibiting tumor-induced weight loss although having only moderate inhibitory effects on tumor growth. Anti-Fn14 antibodies prevented tumor- induced inflammation and loss of fat and muscle mass. Fn14 signaling in the tumor, rather than host, is responsible for inducing this cachexia because tu- mors in Fn14- and TWEAK-deficient hosts developed cachexia that was comparable to that of wild-type mice. These results extend the role of Fn14 in wound repair and muscle development to involvement in the etiology of cachexia and indicate that Fn14 antibodies may be a promising approach to treat cachexia, thereby extending lifespan and improving quality of life for cancer patients.
    Cell 09/2015; 162(6):1365. DOI:10.1016/j.cell.2015.08.031 · 32.24 Impact Factor
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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: Objective: 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. Methods: A multicenter, cross-sectional study was conducted in 448 subjects free from clinical CVD. B-mode ultrasound was performed to detect the presence of carotid and/or femoral atherosclerotic plaques. sTWEAK concentrations were measured by enzyme-linked immunosorbent assay. Results: sTWEAK serum levels were reduced in parallel with an increment in cardiovascular risk factors. sTWEAK concentrations were independently and negatively associated with carotid intima/media thickness. Subjects with atherosclerotic plaques showed a reduction in sTWEAK levels [808 (645-963) vs 993 (830-1278); p < 0.001]. A gradual decrease in sTWEAK levels was observed as the number of atherosclerotic plaques increased in our studied population. When we analyzed sTWEAK levels according to the vascular territory affected, we observed that sTWEAK concentrations were only diminished in subjects with carotid atherosclerotic plaques but not in those with femoral plaques. Following adjustment for various confounders, the OR for presenting carotid atherosclerotic plaque in subjects in lower vs higher tertile of sTWEAK levels was 8.09 [4.30-15.23; median (IQR); p < 0.001]. Conclusions: Diminished sTWEAK concentrations were significantly and independently associated with the presence of carotid atherosclerotic plaques in asymptomatic subjects.
    Atherosclerosis 04/2015; 239(2). DOI:10.1016/j.atherosclerosis.2015.01.040 · 3.99 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 · 8.56 Impact Factor
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