Anti-Fn14 Antibody-Conjugated Nanoparticles Display Membrane TWEAK-Like Agonism.
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ABSTRACT:
SUBMITTER: Aido A
PROVIDER: S-EPMC8308961 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Fibroblast growth factor-inducible 14 (Fn14) is a member of the tumour necrosis factor (TNF) receptor family that is induced in a variety of cell types in situations of tissue injury. Fn14 becomes activated by TNF-like weak inducer of apoptosis (TWEAK), a typical member of the TNF ligand family. TWEAK is constitutively expressed by monocytes and some tumour cell lines and also shows cytokine inducible expression in various other cell types. Fn14 activation results in stimulation of signalling pathways culminating in the activation of NFκB transcription factors and various MAPKs but might also trigger the PI3K/Akt pathway and GTPases of the Rho family. In accordance with its tissue damage-associated expression pattern and its pleiotropic proinflammatory signalling capabilities, the TWEAK-Fn14 system has been implicated in a huge number of pathologies. The use of TWEAK- and Fn14-knockout mice identified the TWEAK-Fn14 system as a crucial player in muscle atrophy, cerebral ischaemia, kidney injury, atherosclerosis and infarction as well as in various autoimmune scenarios including experimental autoimmune encephalitis, rheumatoid arthritis and inflammatory bowel disease. Moreover, there is increasing preclinical evidence that Fn14 targeting is a useful option in tumour therapy. Based on a discussion of the signalling capabilities of TWEAK and Fn14, this review is focused on two major issues. On the one hand, on the molecular and cellular basis of the TWEAK/Fn14-related pathological outcomes in the aforementioned diseases and on the other hand, on the preclinical experience that have been made so far with TWEAK and Fn14 targeting drugs.
| S-EPMC3799590 | biostudies-literature
Project description:The recurrence of prostate cancer metastases to bone after androgen deprivation therapy is a major clinical challenge. We identified FN14 (TNFRSF12A), a TNF receptor family member, as a factor that promotes prostate cancer bone metastasis. In experimental models, depletion of FN14 inhibited bone metastasis, and FN14 could be functionally reconstituted with IKK?-dependent, NF?B signaling activation. In human prostate cancer, upregulated FN14 expression was observed in more than half of metastatic samples. In addition, FN14 expression was correlated inversely with androgen receptor (AR) signaling output in clinical samples. Consistent with this, AR binding to the FN14 enhancer decreased expression. We show here that FN14 may be a survival factor in low AR output prostate cancer cells. Our results define one upstream mechanism, via FN14 signaling, through which the NF?B pathway contributes to prostate cancer metastasis and suggest FN14 as a candidate therapeutic and imaging target for castrate-resistant prostate cancers.
| S-EPMC4429795 | biostudies-literature
Project description:PurposeHeavy-metal chelators and inorganic nanoparticles (NPs) have been examined as potential radioenhancers to increase the efficacy of external beam radiation therapy for various cancers. Most of these agents have, unfortunately, displayed relatively poor pharmacokinetic properties, which limit the percentage of injected dose (%ID/g) that localizes to tumors and which shorten the window for effective radiation enhancement due to rapid tumor washout.Methods and materialsTo address these challenges, we sought to conjugate gadolinium-based ultrasmall (<5 nm) NPs to an antibody directed against the oncogenic MUC1-C subunit that is overexpressed on the surface of many different human cancer types. The binding of the anti-MUC1-C antibody 3D1 to MUC1-C on the surface of a cancer cell is associated with its internalization and, thereby, to effective intracellular delivery of the antibody-associated payload, promoting its effective tumor retention. As such, we examined whether systemically administered anti-MUC1-C antibody-conjugated, gadolinium-based NPs (anti-MUC1-C/NPs) could accumulate within cell-line xenograft models of MUC1-C-expressing (H460) lung and (E0771) breast cancers to improve the efficacy of radiation therapy (XRT).ResultsThe %ID/g of anti-MUC1-C/NPs that accumulated within tumors was found to be similar to that of their unconjugated counterparts (6.6 ± 1.4 vs 5.9 ± 1.7 %ID/g, respectively). Importantly, the anti-MUC1-C/NPs demonstrated prolonged retention in in vivo tumor microenvironments; as a result, the radiation boost was maintained during the course of fractionated therapy (3 × 5.2 Gy). We found that by administering anti-MUC1-C/NPs with XRT, it was possible to significantly augment tumor growth inhibition and to prolong the animals' overall survival (46.2 ± 3.1 days) compared with the administration of control NPs with XRT (31.1 ± 2.4 days) or with XRT alone (27.3 ± 1.6 days; P < .01, log-rank).ConclusionsThese findings suggest that anti-MUC1-C/NPs could be used to enhance the effectiveness of radiation therapy and potentially to improve clinical outcomes.
| S-EPMC7680267 | biostudies-literature
Project description:The incidence of acute kidney injury (AKI) and chronic kidney disease (CKD) is increasing. However, there is no effective therapy for AKI and current approaches only slow down, but do not prevent progression of CKD. TWEAK is a TNF superfamily cytokine. A solid base of preclinical data suggests a role of therapies targeting the TWEAK or its receptor Fn14 in AKI and CKD. In particular TWEAK/Fn14 targeting may preserve renal function and decrease cell death, inflammation, proteinuria, and fibrosis in mouse animal models. Furthermore there is clinical evidence for a role of TWEAK in human kidney injury including increased tissue and/or urinary levels of TWEAK and parenchymal renal cell expression of the receptor Fn14. In this regard, clinical trials of TWEAK targeting are ongoing in lupus nephritis. Nuclear factor-kappa B (NF-?B) activation plays a key role in TWEAK-elicited inflammatory responses. Activation of the non-canonical NF-?B pathway is a critical difference between TWEAK and TNF. TWEAK activation of the non-canonical NF-?B pathways promotes inflammatory responses in tubular cells. However, there is an incomplete understanding of the role of non-canonical NF-?B activation in kidney disease and on its contribution to TWEAK actions in vivo.
| S-EPMC3857575 | biostudies-literature
Project description:Myotonic dystrophy type 1 (DM1), the most prevalent muscular dystrophy in adults, is characterized by progressive muscle wasting and multi-systemic complications. DM1 is the prototype for disorders caused by RNA toxicity. Currently, no therapies exist. Here, we identify that fibroblast growth factor-inducible 14 (Fn14), a member of the tumor necrosis factor receptor super-family, is induced in skeletal muscles and hearts of mouse models of RNA toxicity and in tissues from DM1 patients, and that its expression correlates with severity of muscle pathology. This is associated with downstream signaling through the NF-?B pathways. In mice with RNA toxicity, genetic deletion of Fn14 results in reduced muscle pathology and better function. Importantly, blocking TWEAK/Fn14 signaling with an anti-TWEAK antibody likewise improves muscle histopathology and functional outcomes in affected mice. These results reveal new avenues for therapeutic development and provide proof of concept for a novel therapeutic target for which clinically available therapy exists to potentially treat muscular dystrophy in DM1.
| S-EPMC4355029 | biostudies-literature
Project description:Fibroblast growth factor-inducible protein 14 (Fn14), the cell surface receptor for tumor necrosis factor-like weak inducer of apoptosis (TWEAK), is overexpressed in various human solid tumor types and can be a negative prognostic indicator. We detected Fn14 expression in ?60% of the melanoma cell lines we tested, including both B-Raf WT and B-Raf(V600E) lines. Tumor tissue microarray analysis indicated that Fn14 expression was low in normal skin, but elevated in 173/190 (92%) of primary melanoma specimens and in 86/150 (58%) of melanoma metastases tested. We generated both a chemical conjugate composed of the recombinant gelonin (rGel) toxin and the anti-Fn14 antibody ITEM-4 (designated ITEM4-rGel) and a humanized, dimeric single-chain antibody of ITEM-4 fused to rGel (designated hSGZ). Both ITEM4-rGel and hSGZ were highly cytotoxic to a panel of different melanoma cell lines. Mechanistic studies showed that both immunotoxins induced melanoma cell necrosis. In addition, these immunotoxins could upregulate the cellular expression of Fn14 and trigger cell-signaling events similar to the Fn14 ligand TWEAK. Finally, treatment of mice bearing human melanoma MDA-MB-435 xenografts with either ITEM4-rGel or hSGZ showed significant tumor growth inhibition compared with controls. We conclude that Fn14 is a therapeutic target in melanoma and the hSGZ construct appears to warrant further development as a therapeutic agent against Fn14-positive melanoma.
| S-EPMC3600159 | biostudies-literature
Project description:As a humanized mouse antibody, SM5-1 can target a membrane protein of about 230kDa over-expressed in hepatocellular carcinoma (HCC), melanoma and breast cancer and it has been found to inhibit the progress of tumor cells. In this study, SM5-1 conjugated gold nanoparticles were prepared to study the antitumor efficacy in the treatment of HCC-LM3-fLuc tumor. The results showed that AU-SM5-1 could inhibit HCC-LM3 hepatocellular carcinoma cell proliferation up to 71.26% at the concentration of 0.5mg/ml contrast with SM5-1 and gold nanoparticles. In order to address the mechanism of the antiproliferative effects of AU-SM5-1, we examined the gene expression in HCC-LM3-fLuc tumor cells based on gene-chip screening.
2014-07-11 | GSE59284 | GEO
Project description:TWEAK, a TNF family ligand with pleiotropic cellular functions, was originally described as capable of inducing tumor cell death in vitro. TWEAK functions by binding its receptor, Fn14, which is up-regulated on many human solid tumors. Herein, we show that intratumoral administration of TWEAK, delivered either by an adenoviral vector or in an immunoglobulin Fc-fusion form, results in significant inhibition of tumor growth in a breast xenograft model. To exploit the TWEAK-Fn14 pathway as a therapeutic target in oncology, we developed an anti-Fn14 agonistic antibody, BIIB036. Studies described herein show that BIIB036 binds specifically to Fn14 but not other members of the TNF receptor family, induces Fn14 signaling, and promotes tumor cell apoptosis in vitro. In vivo, BIIB036 effectively inhibits growth of tumors in multiple xenograft models, including colon (WiDr), breast (MDA-MB-231), and gastric (NCI-N87) tumors, regardless of tumor cell growth inhibition response observed to BIIB036 in vitro. The anti-tumor activity in these cell lines is not TNF-dependent. Increasing the antigen-binding valency of BIB036 significantly enhances its anti-tumor effect, suggesting the contribution of higher order cross-linking of the Fn14 receptor. Full Fc effector function is required for maximal activity of BIIB036 in vivo, likely due to the cross-linking effect and/or ADCC mediated tumor killing activity. Taken together, the anti-tumor properties of BIIB036 validate Fn14 as a promising target in oncology and demonstrate its potential therapeutic utility in multiple solid tumor indications.
| S-EPMC3218533 | biostudies-literature
Project description:The TNF superfamily member TWEAK (TNFSF12) is a multifunctional cytokine implicated in physiological tissue regeneration and wound repair. TWEAK is initially synthesized as a membrane-anchored protein, but furin cleavage within the stalk region can generate a secreted TWEAK isoform. Both TWEAK isoforms bind to a small cell surface receptor named Fn14 (TNFRSF12A) and this interaction stimulates various cellular responses, including proliferation and migration. Fn14, like other members of the TNF receptor superfamily, is not a ligand-activated protein kinase. Instead, TWEAK:Fn14 engagement promotes Fn14 association with members of the TNFR associated factor family of adapter proteins, which triggers activation of various signaling pathways, including the classical and alternative NF-?B pathways. Numerous studies have revealed that Fn14 gene expression is significantly elevated in injured tissues and in most solid tumor types. Also, sustained Fn14 signaling has been implicated in the pathogenesis of cerebral ischemia, chronic inflammatory diseases, and cancer. Accordingly, several groups are developing TWEAK- or Fn14-targeted agents for possible therapeutic use in patients. These agents include monoclonal antibodies, fusion proteins, and immunotoxins. In this article, we provide an overview of some of the TWEAK/Fn14 axis-targeted agents currently in pre-clinical animal studies or in human clinical trials and discuss two other potential approaches to target this intriguing signaling node.
| S-EPMC3870272 | biostudies-literature
Project description:The identification of the cellular origins of myofibroblasts has led to the discovery of novel pathways that potentially drive myofibroblast perpetuation in disease. Here, we further investigated the role of innate immune signaling pathways in this process. In mice, renal injury-induced activation of pericytes, which are myofibroblast precursors attached to endothelial cells, led to upregulated expression of TNF receptor superfamily member 12a, also known as fibroblast growth factor-inducible 14 (Fn14), by these cells. In live rat kidney slices, administration of the Fn14 ligand, TNF-related weak inducer of apoptosis (TWEAK), promoted pericyte-dependent vasoconstriction followed by pericyte detachment from capillaries. In vitro, administration of TWEAK activated and differentiated pericytes into cytokine-producing myofibroblasts, and further activated established myofibroblasts in a manner requiring canonical and noncanonical NF-?B signaling pathways. Deficiency of Fn14 protected mouse kidneys from fibrogenesis, inflammation, and associated vascular instability after in vivo injury, and was associated with loss of NF-?B signaling. In a genetic model of spontaneous CKD, therapeutic delivery of anti-TWEAK blocking antibodies attenuated disease progression, preserved organ function, and increased survival. These results identify the TWEAK-Fn14 signaling pathway as an important factor in myofibroblast perpetuation, fibrogenesis, and chronic disease progression.
| S-EPMC5118488 | biostudies-literature