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

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 tiss...

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Bibliographic Details
Published in:Oncogene 2016-04, Vol.35 (17), p.2145-2155
Main Authors: Perez, J G, Tran, N L, Rosenblum, M G, Schneider, C S, Connolly, N P, Kim, A J, Woodworth, G F, Winkles, J A
Format: Article
Language:English
Subjects:
Apoptosis
Apoptosis - genetics
Brain cancer
Brain tumors
Care and treatment
Cell migration
Cell Movement - genetics
Cell receptors
Cell surface
Cellular biology
Chemotherapy
Cytokine TWEAK
Cytotoxic agents
Cytotoxicity
Drug Resistance, Neoplasm - genetics
Fibroblast growth factors
Gene expression
Gene Expression Regulation, Neoplastic
Glioblastoma
Glioblastoma - drug therapy
Glioblastoma - genetics
Glioblastoma - pathology
Glioblastoma - surgery
Glioblastoma multiforme
Glioma cells
Growth factors
Health aspects
Humans
Innovations
Mesenchyme
Molecular targeted therapy
Neoplasm Invasiveness - genetics
Parenchyma
Properties
Receptors, Tumor Necrosis Factor - biosynthesis
Receptors, Tumor Necrosis Factor - genetics
Solid tumors
Tumor necrosis factor
Tumor Necrosis Factor-alpha - genetics
Tumor necrosis factor-TNF
Tumor Necrosis Factors - biosynthesis
Tumor Necrosis Factors - genetics
Tumors
TWEAK Receptor
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Summary: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 'GB multiforme'). 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 is upregulated 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) 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.
ISSN:0950-9232
1476-5594
DOI:10.1038/onc.2015.310