Therapeutic potential of the TWEAK/Fn14 pathway in intractable gastrointestinal cancer

Yoriki,Ryo; Akashi,Satoru; Sho,Masayuki; Nomi,Takeo; Yamato,Ichiro; Hotta,Kiyohiko; Takayama,Tomoyoshi; Matsumoto,Sohei; Wakatsuki,Kohei; Migita,Kazuhiro; Yagita,Hideo; Nakajima,Yoshiyuki

doi:10.3892/etm.2010.181

Therapeutic potential of the TWEAK/Fn14 pathway in intractable gastrointestinal cancer

Authors:
- Ryo Yoriki
- Satoru Akashi
- Masayuki Sho
- Takeo Nomi
- Ichiro Yamato
- Kiyohiko Hotta
- Tomoyoshi Takayama
- Sohei Matsumoto
- Kohei Wakatsuki
- Kazuhiro Migita
- Hideo Yagita
- Yoshiyuki Nakajima
View Affiliations

Affiliations: Department of Surgery, Nara Medical University, Nara 634-8522, Japan, Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan
Published online on: December 2, 2010 https://doi.org/10.3892/etm.2010.181
Pages: 103-108

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is a member of the TNF superfamily. It has been suggested that it plays a pivotal role in various physiological and pathological conditions due to its proinflammatory properties. Fibroblast growth-inducible 14 (Fn14) has been identified as a TWEAK receptor. A number of studies have suggested that TWEAK-Fn14 interaction results in the promotion of apoptosis, cell growth as well as angiogenesis. Although recent studies have indicated that TWEAK and Fn14 are expressed in a number of tumor lines and tissues, the therapeutic potential of this pathway has yet to be elucidated. This study investigated the potential of TWEAK and Fn14 in esophageal and pancreatic cancer as novel molecular targets for anti-cancer therapy. TWEAK and Fn14 protein expression was evaluated in 43 patients with esophageal cancer and 51 patients with pancreatic cancer by immunohistochemistry. As a result, either TWEAK or Fn14 expression was observed in 58.1% of the cases with esophageal cancer and 74.5% of the cases with pancreatic cancer. Furthermore, TWEAK/Fn14 gene expression was identified in the majority of the human esophageal and pancreatic cancer cell lines. Therapeutic efficacies of blocking TWEAK and Fn14 were evaluated by tumor growth inhibition assay in TWEAK- and Fn14-expressing human esophageal and pancreatic cancer cell lines. Coculture with anti-TWEAK or -Fn14 mAb was found to induce a 22-65% cell growth inhibition of these cells. Finally, the significant therapeutic effect of targeting this pathway under in vivo physiological conditions was confirmed using a murine gastrointestinal cancer model. In conclusion, the TWEAK/Fn14 pathway may be functional and critical in intractable gastrointestinal cancers. Therefore, TWEAK and/or Fn14 may be novel molecular targets for anti-cancer therapy.

View Figures

View References

1.	Jemal A, Siegel R, Xu J and Ward E: Cancer statistics, 2010. CA Cancer J Clin. 60:277–300. 2010. View Article : Google Scholar
2.	Kamangar F, Dores GM and Anderson WF: Patterns of cancer incidence, mortality, and prevalence across five continents: defining priorities to reduce cancer disparities in different geographic regions of the world. J Clin Oncol. 24:2137–2150. 2006. View Article : Google Scholar
3.	Li D, Xie K, Wolff R and Abbruzzese JL: Pancreatic cancer. Lancet. 363:1049–1057. 2004. View Article : Google Scholar
4.	Chicheportiche Y, Bourdon PR, Xu H, Hsu YM, Scott H, Hession C, Garcia I and Browning JL: TWEAK, a new secreted ligand in the tumor necrosis factor family that weakly induces apoptosis. J Biol Chem. 272:32401–32410. 1997. View Article : Google Scholar : PubMed/NCBI
5.	Winkles JA: The TWEAK-Fn14 cytokine-receptor axis: discovery, biology and therapeutic targeting. Nat Rev Drug Discov. 7:411–425. 2008. View Article : Google Scholar : PubMed/NCBI
6.	Wiley SR, Cassiano L, Lofton T, Davis-Smith T, Winkles JA, Lindner V, Liu H, Daniel TO, Smith CA and Fanslow WC: A novel TNF receptor family member binds TWEAK and is implicated in angiogenesis. Immunity. 15:837–846. 2001. View Article : Google Scholar : PubMed/NCBI
7.	Kumar M, Makonchuk DY, Li H, Mittal A and Kumar A: TNF-like weak inducer of apoptosis (TWEAK) activates proinflammatory signaling pathways and gene expression through the activation of TGF-beta-activated kinase 1. J Immunol. 182:2439–2448. 2009. View Article : Google Scholar : PubMed/NCBI
8.	Polek TC, Talpaz M, Darnay BG and Spivak-Kroizman T: TWEAK mediates signal transduction and differentiation of RAW264.7 cells in the absence of Fn14/TweakR. Evidence for a second TWEAK receptor. J Biol Chem. 278:32317–32323. 2003. View Article : Google Scholar : PubMed/NCBI
9.	Harada N, Nakayama M, Nakano H, Fukuchi Y, Yagita H and Okumura K: Pro-inflammatory effect of TWEAK/Fn14 interaction on human umbilical vein endothelial cells. Biochem Biophys Res Commun. 299:488–493. 2002. View Article : Google Scholar : PubMed/NCBI
10.	Zhao Z, Burkly LC, Campbell S, Schwartz N, Molano A, Choudhury A, Eisenberg RA, Michaelson JS and Putterman C: TWEAK/Fn14 interactions are instrumental in the pathogenesis of nephritis in the chronic graft-versus-host model of systemic lupus erythematosus. J Immunol. 179:7949–7958. 2007. View Article : Google Scholar : PubMed/NCBI
11.	Desplat-Jego S, Creidy R, Varriale S, Allaire N, Luo Y, Bernard D, Hahm K, Burkly L and Boucraut J: Anti-TWEAK monoclonal antibodies reduce immune cell infiltration in the central nervous system and severity of experimental auto-immune encephalomyelitis. Clin Immunol. 117:15–23. 2005. View Article : Google Scholar : PubMed/NCBI
12.	Perper SJ, Browning B, Burkly LC, et al: TWEAK is a novel arthritogenic mediator. J Immunol. 177:2610–2620. 2006. View Article : Google Scholar : PubMed/NCBI
13.	Kamata K, Kamijo S, Nakajima A, Koyanagi A, Kurosawa H, Yagita H and Okumura K: Involvement of TNF-like weak inducer of apoptosis in the pathogenesis of collagen-induced arthritis. J Immunol. 177:6433–6439. 2006. View Article : Google Scholar : PubMed/NCBI
14.	Kawakita T, Shiraki K, Yamanaka Y, Yamaguchi Y, Saitou Y, Enokimura N, Yamamoto N, Okano H, Sugimoto K, Murata K and Nakano T: Functional expression of TWEAK in human colonic adenocarcinoma cells. Int J Oncol. 26:87–93. 2005.PubMed/NCBI
15.	Kawakita T, Shiraki K, Yamanaka Y, Yamaguchi Y, Saitou Y, Enokimura N, Yamamoto N, Okano H, Sugimoto K, Murata K and Nakano T: Functional expression of TWEAK in human hepatocellular carcinoma: possible implication in cell proliferation and tumor angiogenesis. Biochem Biophys Res Commun. 318:726–733. 2004. View Article : Google Scholar : PubMed/NCBI
16.	Tran NL, McDonough WS, Savitch BA, et al: Increased fibroblast growth factor-inducible 14 expression levels promote glioma cell invasion via Rac1 and nuclear factor-kappaB and correlate with poor patient outcome. Cancer Res. 66:9535–9542. 2006. View Article : Google Scholar : PubMed/NCBI
17.	Han H, Bearss DJ, Browne LW, Calaluce R, Nagle RB and von Hoff DD: Identification of differentially expressed genes in pancreatic cancer cells using cDNA microarray. Cancer Res. 62:2890–2896. 2002.PubMed/NCBI
18.	Feng SL, Guo Y, Factor VM, Thorgeirsson SS, Bell DW, Testa JR, Peifley KA and Winkles JA: The Fn14 immediate-early response gene is induced during liver regeneration and highly expressed in both human and murine hepatocellular carcinomas. Am J Pathol. 156:1253–1261. 2000. View Article : Google Scholar
19.	Culp PA, Choi D, Zhang Y, et al: Antibodies to TWEAK receptor inhibit human tumor growth through dual mechanisms. Clin Cancer Res. 16:497–508. 2010. View Article : Google Scholar : PubMed/NCBI
20.	Tran NL, McDonough WS, Savitch BA, Sawyer TF, Winkles JA and Berens ME: The tumor necrosis factor-like weak inducer of apoptosis (TWEAK)-fibroblast growth factor-inducible 14 (Fn14) signaling system regulates glioma cell survival via NFkappaB pathway activation and BCL-XL/BCL-W expression. J Biol Chem. 280:3483–3492. 2005. View Article : Google Scholar
21.	Ho DH, Vu H, Brown SA, Donohue PJ, Hanscom HN and Winkles JA: Soluble tumor necrosis factor-like weak inducer of apoptosis overexpression in HEK293 cells promotes tumor growth and angiogenesis in athymic nude mice. Cancer Res. 64:8968–8972. 2004. View Article : Google Scholar : PubMed/NCBI
22.	Winkles JA, Tran NL and Berens ME: TWEAK and Fn14: new molecular targets for cancer therapy? Cancer Lett. 235:11–17. 2006. View Article : Google Scholar : PubMed/NCBI
23.	Polavarapu R, Gongora MC, Winkles JA and Yepes M: Tumor necrosis factor-like weak inducer of apoptosis increases the permeability of the neurovascular unit through nuclear factor-kappa B pathway activation. J Neurosci. 25:10094–10100. 2005. View Article : Google Scholar : PubMed/NCBI
24.	Potrovita I, Zhang W, Burkly L, Hahm K, Lincecum J, Wang MZ, Maurer MH, Rossner M, Schneider A and Schwaninger M: Tumor necrosis factor-like weak inducer of apoptosis-induced neurodegeneration. J Neurosci. 24:8237–8244. 2004. View Article : Google Scholar : PubMed/NCBI
25.	Nakayama M, Harada N, Okumura K and Yagita H: Characterization of murine TWEAK and its receptor (Fn14) by monoclonal antibodies. Biochem Biophys Res Commun. 306:819–825. 2003. View Article : Google Scholar : PubMed/NCBI
26.	Nakayama M, Ishidoh K, Kojima Y, Harada N, Kominami E, Okumura K and Yagita H: Fibroblast growth factor-inducible 14 mediates multiple pathways of TWEAK-induced cell death. J Immunol. 170:341–348. 2003. View Article : Google Scholar : PubMed/NCBI
27.	Han S, Yoon K, Lee K, Kim K, Jang H, Lee NK, Hwang K and Young Lee S: TNF-related weak inducer of apoptosis receptor, a TNF receptor superfamily member, activates NF-kappa B through TNF receptor-associated factors. Biochem Biophys Res Commun. 305:789–796. 2003. View Article : Google Scholar : PubMed/NCBI
28.	Watts GS, Tran NL, Berens ME, Bhattacharyya AK, Nelson MA, Montgomery EA and Sampliner RE: Identification of Fn14/TWEAK receptor as a potential therapeutic target in esophageal adenocarcinoma. Int J Cancer. 121:2132–2139. 2007. View Article : Google Scholar : PubMed/NCBI
29.	Wang D, Fung JN, Tuo Y, Hu L and Chen C: TWEAK/Fn14 promotes apoptosis of human endometrial cancer cells via caspase pathway. Cancer Lett. 294:91–100. 2010. View Article : Google Scholar : PubMed/NCBI
30.	Jakubowski A, Ambrose C, Parr M, Lincecum JM, Wang MZ, Zheng TS, Browning B, Michaelson JS, Baetscher M, Wang B, Bissell DM and Burkly LC: TWEAK induces liver progenitor cell proliferation. J Clin Invest. 115:2330–2340. 2005. View Article : Google Scholar : PubMed/NCBI
31.	Tanabe K, Bonilla I, Winkles JA and Strittmatter SM: Fibroblast growth factor-inducible-14 is induced in axotomized neurons and promotes neurite outgrowth. J Neurosci. 23:9675–9686. 2003.PubMed/NCBI
32.	Girgenrath M, Weng S, Kostek CA, et al: TWEAK, via its receptor Fn14, is a novel regulator of mesenchymal progenitor cells and skeletal muscle regeneration. EMBO J. 25:5826–5839. 2006. View Article : Google Scholar : PubMed/NCBI
33.	Moore MJ, Goldstein D, Hamm J, et al: Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 25:1960–1966. 2007. View Article : Google Scholar