Regulation of Fibroblast Growth Factor-inducible 14 (Fn14) Expression Levels via Ligand-independent Lysosomal Degradation

S, Gurunathan; Winkles, Jeffrey A.; Ghosh, Sankar; Hayden, Matthew S.

doi:10.1074/jbc.m114.563478

Cited by 26 publications

(27 citation statements)

References 63 publications

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“…Lower Fn14 levels are present in tumor core regions, where surgery is often successful [21]. Importantly, Fn14 undergoes constitutive receptor internalization, which could facilitate therapeutic agent entry into target cells [36]. These findings warrant further exploration of Fn14 for invasive GBM-targeted therapeutics as well as inhibition of brain cancer invasion mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Decreased non-specific adhesivity, receptor targeted (DART) nanoparticles exhibit improved dispersion, cellular uptake, and tumor retention in invasive gliomas

Wadajkar

Dancy

Roberts

et al. 2017

Journal of Controlled Release

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The most common and deadly form of primary brain cancer, glioblastoma (GBM), is characterized by significant intratumoral heterogeneity, microvascular proliferation, immune system suppression, and brain tissue invasion. Delivering effective and sustained treatments to the invasive GBM cells intermixed with functioning neural elements is a major goal of advanced therapeutic systems for brain cancer. Previously, we investigated the nanoparticle characteristics that enable targeting of invasive GBM cells. This revealed the importance of minimizing non-specific binding within the relatively adhesive, ‘sticky’ microenvironment of the brain and brain tumors in particular. We refer to such nanoformulations with decreased non-specific adhesivity and receptor targeting as ‘DART’ therapeutics. In this work, we applied this information towards the design and characterization of biodegradable nanocarriers, and in vivo testing in orthotopic experimental gliomas. We formulated particulate nanocarriers using poly(lactic-co-glycolic acid) (PLGA) and PLGA-polyethylene glycol (PLGA-PEG) polymers to generate sub-100 nm nanoparticles with minimal binding to extracellular brain components and strong binding to the Fn14 receptor – an upregulated, conserved component in invasive GBM. Multiple particle tracking in brain tissue slices and in vivo testing in orthotopic murine malignant glioma revealed preserved nanoparticle diffusivity and increased uptake in brain tumor cells. These combined characteristics also resulted in longer retention of the DART nanoparticles within the orthotopic tumors compared to non-targeted versions. Taken together, these results and nanoparticle design considerations offer promising new methods to optimize therapeutic nanocarriers for improving drug delivery and treatment for invasive brain tumors.

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Section: Discussionmentioning

confidence: 99%

Decreased non-specific adhesivity, receptor targeted (DART) nanoparticles exhibit improved dispersion, cellular uptake, and tumor retention in invasive gliomas

Wadajkar

Dancy

Roberts

et al. 2017

Journal of Controlled Release

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“…U87-Luc/GFP cells were cultured at 37°C and 5% CO 2 in DMEM (Invitrogen Corp., Carlsbad, CA) supplemented with 10% fetal bovine serum (FBS, Invitrogen Corp.), 0.5 mg/mL G418, and 1% penicillin/streptomycin (Invitrogen Corp.). A mouse embryonic fibroblast (MEF) cell line generated from Fn14-null mice (MEF 3.5−/−) and a derivative stably transfected MEF 3.5−/− cell line expressing human Fn14 (MEF Fn14-V5) [40] were provided by Dr. Matthew Hayden (Columbia University Medical Center). Both cell lines were maintained at 37°C and 5% CO 2 in DMEM supplemented with 10% FBS and 1% penicillin/streptomycin; the Fn14-V5 cell media also contained 10 ug/ml blasticidin.…”

Section: Methodsmentioning

confidence: 99%

Minimizing the non-specific binding of nanoparticles to the brain enables active targeting of Fn14-positive glioblastoma cells

et al. 2015

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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.

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“…The proposal that Fn14 may be an excellent drug delivery portal is supported by recent work by Gurunathan et al demonstrating that the steady-state Fn14 expression level in most cells reflects a dynamic process, whereby Fn14 is constitutively synthesized, trafficked to the plasma membrane, internalized, and degraded. 122 In particular, constitutive Fn14 expression and endocytosis may result in more efficient and sustained delivery of Fn14-targeted therapeutics into the intracellular compartment.…”

Section: Therapeutic Strategies That Leverage Fn14 Overexpression Inmentioning

confidence: 99%

The TWEAK receptor Fn14 is a potential cell surface portal for targeted delivery of glioblastoma therapeutics

et al. 2015

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Fibroblast growth factor-inducible 14 (Fn14; TNFRSF12A) is the cell surface receptor for the tumor necrosis factor (TNF) family member TNF-like weak inducer of apoptosis (TWEAK). The Fn14 gene is normally expressed at low levels in healthy tissues but expression is significantly increased after tissue injury and in many solid tumor types, including glioblastoma (GB; formerly referred to as ‘glioblastoma multiforme’ or GBM). GB is the most common and aggressive primary malignant brain tumor, and the current standard-of-care therapeutic regimen has a relatively small impact on patient survival, primarily because glioma cells have an inherent propensity to invade into normal brain parenchyma, which invariably leads to tumor recurrence and patient death. Despite major, concerted efforts to find new treatments, a new GB therapeutic that improves survival has not been introduced since 2005. In this review article, we summarize studies indicating that (i) Fn14 gene expression is low in normal brain tissue but up-regulated in advanced brain cancers and, in particular, in GB tumors exhibiting the mesenchymal molecular subtype, (ii) Fn14 expression can be detected in glioma cells residing in both the tumor core and invasive rim regions, with the maximal levels found in the invading glioma cells located within normal brain tissue, and (iii) TWEAK:Fn14 engagement as well as Fn14 overexpression can stimulate glioma cell migration, invasion, and resistance to chemotherapeutic agents in vitro. We also discuss two new therapeutic platforms that are currently in development that leverage Fn14 overexpression in GB tumors as a way to deliver cytotoxic agents to the glioma cells remaining after surgical resection while sparing normal healthy brain cells.

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Regulation of Fibroblast Growth Factor-inducible 14 (Fn14) Expression Levels via Ligand-independent Lysosomal Degradation

Cited by 26 publications

References 63 publications

Decreased non-specific adhesivity, receptor targeted (DART) nanoparticles exhibit improved dispersion, cellular uptake, and tumor retention in invasive gliomas

Decreased non-specific adhesivity, receptor targeted (DART) nanoparticles exhibit improved dispersion, cellular uptake, and tumor retention in invasive gliomas

Minimizing the non-specific binding of nanoparticles to the brain enables active targeting of Fn14-positive glioblastoma cells

The TWEAK receptor Fn14 is a potential cell surface portal for targeted delivery of glioblastoma therapeutics

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