Abstract
BackgroundNew 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.ResultsFn14•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.ConclusionsIn 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.
Highlights
Hepatocellular cancer (HCC, hepatoma) is one of the most common solid tumors, fifth in incidence worldwide [1]
Fn14TRAIL protein characterization Fn14TRAIL was produced as described in the materials and methods section
Purity and identity were verified by coommassie SDS-PAGE staining and western blot analysis with anti Fn14 and anti TRAIL antibodies (Figure 1 B and C)
Summary
Hepatocellular cancer (HCC, hepatoma) is one of the most common solid tumors, fifth in incidence worldwide [1]. The net balance of positive and negative intercellular signaling dictates tumor cell proliferation and survival, and proteins of the tumor necrosis factor (TNF) superfamily loom large in this array of regulatory signaling inputs [3]. TNF superfamily proteins contribute to tissue homeostasis via effects on cell survival, death and differentiation. In the context of HCC and various other tumor types, two members of the TNF superfamily may have special significance, namely, the cell surface ligands TWEAK (TNF-related weak inducer of apoptosis) and TRAIL (TNF-related apoptosis ligand). The counter receptor for TWEAK, Fn14 (fibroblast growth –factor-inducible 14kD protein), is a membrane bound type 1 protein that is expressed on a large variety of cells [5]. Whereas hepatocytes do not normally express Fn14 mRNA or protein, HCC cells and hepatocytes of regenerating liver express significant amounts of them [6] 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
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