title: Fn14•TRAIL effectively inhibits hepatocellular carcinoma growth.
abstract: BACKGROUND
  New strategies for the treatment of hepatocellular carcinoma (HCC) are needed, given that currently available chemotherapeutics are inefficient. Since tumor growth reflects the net balance between pro-proliferative and death signaling, agents shifting the equilibrium toward the latter are of considerable interest. The TWEAK:Fn14 signaling axis promotes tumor cell proliferation and tumor angiogenesis, while TRAIL:TRAIL-receptor (TRAIL-R) interactions selectively induce apoptosis in malignant cells. Fn14•TRAIL, a fusion protein bridging these two pathways, has the potential to inhibit tumor growth, by interfering with TWEAK:Fn14 signaling, while at the same time enforcing TRAIL:TRAIL-R-mediated apoptosis. Consequently, Fn14•TRAIL's capacity to inhibit HCC growth was tested.
  
  
  RESULTS
  Fn14•TRAIL induced robust apoptosis of multiple HCC cell lines, while sparing non-malignant hepatocyte cell lines. Differential susceptibility to this agent did not correlate with expression levels of TRAIL, TRAIL-R, TWEAK and Fn14 by these lines. Fn14•TRAIL was more potent than soluble TRAIL, soluble Fn14, or a combination of the two. The requirement of both of Fn14•TRAIL's molecular domains for function was established using blocking antibodies directed against each of them. Subcutaneous injection of Fn14•TRAIL abrogated HCC growth in a xenograft model, and was well tolerated by the mice.
  
  
  CONCLUSIONS
  In this study, Fn14•TRAIL, a multifunctional fusion protein originally designed to treat autoimmunity, was shown to inhibit the growth of HCC, both in vitro and in vivo. The demonstration of this fusion protein's potent anti-tumor activity suggests that simultaneous targeting of two signaling axes by a single fusion can serve as a basis for highly effective anti-cancer therapies.
authors.affiliation: Nephrology and Hypertension Services, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Aronin
authors.forename: Shira
authors.initials: S
authors.lastname: Amsili
authors.forename: Tatyana B
authors.initials: TB
authors.lastname: Prigozhina
authors.forename: Kobi
authors.initials: K
authors.lastname: Tzdaka
authors.forename: Jacob
authors.initials: J
authors.lastname: Rachmilewitz
authors.forename: Noam
authors.initials: N
authors.lastname: Shani
authors.forename: Mark L
authors.initials: ML
authors.lastname: Tykocinski
authors.forename: Michal
authors.initials: M
authors.lastname: Dranitzki Elhalel
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000074049:Cytokine TWEAK; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008113:Liver Neoplasms / Q000473:pathology*; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000737:chemistry / Q000235:genetics*; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D012995:Solubility; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000737:chemistry / Q000235:genetics* / Q000494:pharmacology*; D000074050:TWEAK Receptor; D048069:Tumor Necrosis Factors / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D000074049:Cytokine TWEAK; D012333:RNA, Messenger; D018124:Receptors, Tumor Necrosis Factor; D011993:Recombinant Fusion Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C000613297:TNFRSF12A protein, human; C109743:TNFSF12 protein, human; D000074050:TWEAK Receptor; C000613299:Tnfrsf12a protein, mouse; D048069:Tumor Necrosis Factors