Abstract
The aim of this current study was to investigate the expression of the tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) and its receptor fibroblast growth factor-inducible 14 (Fn14) in human malignant ovarian tumors, and test TWEAK’s potential role on tumor progression in cell models in-vitro. Using immunohistochemistry (IHC), we found that TWEAK and its receptor Fn14 were expressed in human malignant ovarian tumors, but not in normal ovarian tissues or in borderline/benign epithelial ovarian tumors. High levels of TWEAK expression was detected in the majority of malignant tumors (36 out of 41, 87.80%). Similarly, 35 out of 41 (85.37%) malignant ovarian tumors were Fn14 positive. In these malignant ovarian tumors, however, TWEAK/Fn14 expression was not corrected with patients’ clinical subtype/stages or pathological features. In vitro, we demonstrated that TWEAK only inhibited ovarian cancer HO-8910PM cell proliferation in combination with tumor necrosis factor-α (TNF-α), whereas either TWEAK or TNF-α alone didn’t affect HO-8910PM cell growth. TWEAK promoted TNF-α production in cultured THP-1 macrophages. Meanwhile, conditioned media from TWEAK-activated macrophages inhibited cultured HO-8910PM cell proliferation and invasion. Further, TWEAK increased monocyte chemoattractant protein-1 (MCP-1) production in cultured HO-8910PM cells to possibly recruit macrophages. Our results suggest that TWEAK/Fn14, by activating macrophages, could be ovarian tumor suppressors. The unique expression of TWEAK/Fn14 in malignant tumors indicates that it might be detected as a malignant ovarian tumor marker.
Highlights
The tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) was first described as a member of the tumor necrosis factor (TNF) superfamily in 1997 [1]
The present study explored the effect of TWEAK on macrophages, and the subsequent effects of TWEAK and macrophage-derived tumor necrosis factor-a (TNF-a) on ovarian cancer cell proliferation and metastasis
We didn’t see significant TWEAK expression in normal ovarian tissues, or in borderline/ benign tumors (Figure 5A–D). These results suggest that TWEAK is uniquely expressed only in malignant ovarian tumor tissues
Summary
The tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) was first described as a member of the tumor necrosis factor (TNF) superfamily in 1997 [1]. TWEAK was initially identified as a weak inducer of apoptosis in transformed cell lines [2,3]. It is well-accepted that TWEAK is a multifunctional cytokine depending on conditions and cell types [4], soluble TWEAK stimulates murine astrocytes and human HepG2 cells proliferation [5,6], murine RAW264.7 cell differentiation [7], and induces HSC3 cell death [8]. Fibroblast growth factor-inducible 14 (Fn14), the TWEAK receptor [14], is expressed in multiple tumor tissues [15,16]. The expression of TWEAK/Fn14 and their potential function in ovarian tumors are not fully defined
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