Protein & Cell

, Volume 4, Issue 5, pp 393–401 | Cite as

TNFR-1 on tumor cells contributes to the sensitivity of fibrosarcoma to chemotherapy

  • Jingjing Deng
  • Xiaopu Zhao
  • Lijie Rong
  • Xiao Li
  • Xiaoman Liu
  • Zhihai Qin
Research article


Impaired tumor necrosis factor receptor-1 (TNFR-1) signaling has been found in some malignant tumors with poor prognosis. However, the exact role of TNFR-1 signaling in fibrosarcoma remains unclear. Here, we explored the question by comparing the growth of TNFR-1 deficient (Tnfr1) and TNFR-1 competent (Tnfr1+) fibrosarcoma FB61 cells (FB61-m and FB61-R1) in mice. TNFR-1 expression on fibrosarcoma cells delayed their growth in vivo but not in vitro. Moreover, reduced FB61-R1 tumor growth was also obtained in TNFR-1 knockout mice. The mechanism relies mainly on the TNFR-1-mediated downregulation of vascular endothelial growth factor (VEGF) production by tumor cells. Importantly, treatment of FB61-m tumors with melphalan resulted in a short delay of tumor growth, followed by a quick remission. However, when FB61-R1 tumors were treated with melphalan, tumor growth was similarly delayed at first and then completely rejected. Our results reveal evidence for TNFR-1 on tumor cells as a prerequisite in chemotherapy for fibrosarcoma, and provide novel insight into the therapeutic approach against some types of tumors using TNFR-1 angonist.


TNFR-1 fibrosarcoma chemotherapy 


  1. Aggarwal, B.B. (2003). Signalling pathways of the TNF superfamily: a double-edged sword. Nat Rev Immunol 3, 745–756.CrossRefGoogle Scholar
  2. Balkwill, F. (2006). TNF-alpha in promotion and progression of cancer. Cancer Metastasis Rev 25, 409–416.CrossRefGoogle Scholar
  3. Balkwill, F. (2009). Tumour necrosis factor and cancer. Nat Rev Cancer 9, 361–371.CrossRefGoogle Scholar
  4. Bauer, S., Oosterwijk-Wakka, J.C., Adrian, N., Oosterwijk, E., Fischer, E., Wuest, T., Stenner, F., Perani, A., Cohen, L., Knuth, A., et al. (2009). Targeted therapy of renal cell carcinoma: synergistic activity of cG250-TNF and IFNg. Int J Cancer 125, 115–123.CrossRefGoogle Scholar
  5. Blankenstein, T., Qin, Z.H., Uberla, K., Muller, W., Rosen, H., Volk, H.D., and Diamantstein, T. (1991). Tumor suppression after tumor celltargeted tumor necrosis factor alpha gene transfer. J Exp Med 173, 1047–1052.CrossRefGoogle Scholar
  6. Cabal-Hierro, L., and Lazo, P.S. (2012). Signal transduction by tumor necrosis factor receptors. Cell Signal 24, 1297–1305.CrossRefGoogle Scholar
  7. Coffin, C.M., and Alaggio, R. (2012). Fibroblastic and myofibroblastic tumors in children and adolescents. Pediatr Dev Pathol 15, 127–180.CrossRefGoogle Scholar
  8. Dong, H.P., Kleinberg, L., Silins, I., Florenes, V.A., Trope, C.G., Risberg, B., Nesland, J.M., and Davidson, B. (2008). Death receptor expression is associated with poor response to chemotherapy and shorter survival in metastatic ovarian carcinoma. Cancer 112, 84–93.CrossRefGoogle Scholar
  9. Edelblum, K.L., Goettel, J.A., Koyama, T., McElroy, S.J., Yan, F., and Polk, D.B. (2008). TNFR1 promotes tumor necrosis factor-mediated mouse colon epithelial cell survival through RAF activation of NFkappaB. J Biol Chem 283, 29485–29494.CrossRefGoogle Scholar
  10. Fan, F., Gray, M.J., Dallas, N.A., Yang, A.D., Van Buren, G., 2nd, Camp, E.R., and Ellis, L.M. (2008). Effect of chemotherapeutic stress on induction of vascular endothelial growth factor family members and receptors in human colorectal cancer cells. Mol Cancer Ther 7, 3064–3070.CrossRefGoogle Scholar
  11. Ferrara, N., Gerber, H.P., and LeCouter, J. (2003). The biology of VEGF and its receptors. Nat Med 9, 669–676.CrossRefGoogle Scholar
  12. Green, D.R., Ferguson, T., Zitvogel, L., and Kroemer, G. (2009). Immunogenic and tolerogenic cell death. Nat Rev Immunol 9, 353–363.CrossRefGoogle Scholar
  13. Kepp, O., Tesniere, A., Schlemmer, F., Michaud, M., Senovilla, L., Zitvogel, L., and Kroemer, G. (2009a). Immunogenic cell death modalities and their impact on cancer treatment. Apoptosis 14, 364–375.CrossRefGoogle Scholar
  14. Kepp, O., Tesniere, A., Zitvogel, L., and Kroemer, G. (2009b). The immunogenicity of tumor cell death. Curr Opin Oncol 21, 71–76.CrossRefGoogle Scholar
  15. Levine, S.J. (2008). Molecular mechanisms of soluble cytokine receptor generation. J Biol Chem 283, 14177–14181.CrossRefGoogle Scholar
  16. Li, J., Chen, L., and Qin, Z. (2012). Multifaceted tumor stromal fibroblasts. Cancer Microenviron 5, 187–193.CrossRefGoogle Scholar
  17. Li, J., Zhang, W., Jiao, L., Duan, M.H., Guan, H.Z., Zhu, W.G., Tian, Z., and Zhou, D.B. (2011). Combination of melphalan and dexamethasone for patients with newly diagnosed POEMS syndrome. Blood 117, 6445–6449.CrossRefGoogle Scholar
  18. Li, Z., Chen, L., and Qin, Z. (2009). Paradoxical roles of IL-4 in tumor immunity. Cell Mol Immunol 6, 415–422.CrossRefGoogle Scholar
  19. Li, Z., Jiang, J., Wang, Z., Zhang, J., Xiao, M., Wang, C., Lu, Y., and Qin, Z. (2008). Endogenous interleukin-4 promotes tumor development by increasing tumor cell resistance to apoptosis. Cancer Res 68, 8687–8694.CrossRefGoogle Scholar
  20. Lu, Y., Yang, W., Qin, C., Zhang, L., Deng, J., Liu, S., and Qin, Z. (2009). Responsiveness of stromal fibroblasts to IFN-gamma blocks tumor growth via angiostasis. J Immunol 183, 6413–6421.CrossRefGoogle Scholar
  21. Mocellin, S., Rossi, C.R., Pilati, P., and Nitti, D. (2005). Tumor necrosis factor, cancer and anticancer therapy. Cytokine Growth Factor Rev 16, 35–53.CrossRefGoogle Scholar
  22. Ogata, Y., Matono, K., Mizobe, T., Ishibashi, N., Mori, S., Akagi, Y., Ikeda, S., Ozasa, H., Murakami, H., and Shirouzu, K. (2006). The expression of vascular endothelial growth factor determines the efficacy of post-operative adjuvant chemotherapy using oral fluoropyrimidines in stage II or III colorectal cancer. Oncol Rep 15, 1111–1116.Google Scholar
  23. Orbach, D., Rey, A., Cecchetto, G., Oberlin, O., Casanova, M., Thebaud, E., Scopinaro, M., Bisogno, G., Carli, M., and Ferrari, A. (2010). Infantile fibrosarcoma: management based on the European experience. J Clin Oncol 28, 318–323.CrossRefGoogle Scholar
  24. Orbach, D., Rey, A., Oberlin, O., Sanchez de Toledo, J., Terrier-Lacombe, M.J., van Unnik, A., Quintana, E., and Stevens, M.C. (2005). Soft tissue sarcoma or malignant mesenchymal tumors in the first year of life: experience of the International Society of Pediatric Oncology (SIOP) Malignant Mesenchymal Tumor Committee. J Clin Oncol 23, 4363–4371.CrossRefGoogle Scholar
  25. Ouaaz, F., Arron, J., Zheng, Y., Choi, Y., and Beg, A.A. (2002). Dendritic cell development and survival require distinct NF-kappaB subunits. Immunity 16, 257–270.CrossRefGoogle Scholar
  26. Palumbo, A., Bringhen, S., Caravita, T., Merla, E., Capparella, V., Callea, V., Cangialosi, C., Grasso, M., Rossini, F., Galli, M., et al. (2006). Oral melphalan and prednisone chemotherapy plus thalidomide compared with melphalan and prednisone alone in elderly patients with multiple myeloma: randomised controlled trial. Lancet 367, 825–831.CrossRefGoogle Scholar
  27. Qin, Y., Auh, S., Blokh, L., Long, C., Gagnon, I., and Hamann, K.J. (2007). TNF-alpha induces transient resistance to Fas-induced apoptosis in eosinophilic acute myeloid leukemia cells. Cell Mol Immunol 4, 43–52.Google Scholar
  28. Qin, Z., and Blankenstein, T. (2000). CD4+ T cell—mediated tumor rejection involves inhibition of angiogenesis that is dependent on IFN gamma receptor expression by nonhematopoietic cells. Immunity 12, 677–686.CrossRefGoogle Scholar
  29. Qin, Z., Kruger-Krasagakes, S., Kunzendorf, U., Hock, H., Diamantstein, T., and Blankenstein, T. (1993). Expression of tumor necrosis factor by different tumor cell lines results either in tumor suppression or augmented metastasis. J Exp Med 178, 355–360.CrossRefGoogle Scholar
  30. Rauert, H., Stuhmer, T., Bargou, R., Wajant, H., and Siegmund, D. (2011). TNFR1 and TNFR2 regulate the extrinsic apoptotic pathway in myeloma cells by multiple mechanisms. Cell Death Dis 2, e194.CrossRefGoogle Scholar
  31. Riedel, F., Gotte, K., Goessler, U., Sadick, H., and Hormann, K. (2004). Targeting chemotherapy-induced VEGF up-regulation by VEGF antisense oligonucleotides in HNSCC cell lines. Anticancer Res 24, 2179–2183.Google Scholar
  32. Rivas, M.A., Carnevale, R.P., Proietti, C.J., Rosemblit, C., Beguelin, W., Salatino, M., Charreau, E.H., Frahm, I., Sapia, S., Brouckaert, P., et al. (2008). TNF alpha acting on TNFR1 promotes breast cancer growth via p42/P44 MAPK, JNK, Akt and NF-kappa B-dependent pathways. Exp Cell Res 314, 509–529.CrossRefGoogle Scholar
  33. Ruegg, C., Yilmaz, A., Bieler, G., Bamat, J., Chaubert, P., and Lejeune, F.J. (1998). Evidence for the involvement of endothelial cell integrin alphaVbeta3 in the disruption of the tumor vasculature induced by TNF and IFN-gamma. Nat Med 4, 408–414.CrossRefGoogle Scholar
  34. Schutze, S., Tchikov, V., and Schneider-Brachert, W. (2008). Regulation of TNFR1 and CD95 signalling by receptor compartmentalization. Nat Rev Mol Cell Biol 9, 655–662.CrossRefGoogle Scholar
  35. Sha, S., Jin, H., Li, X., Yang, J., Ai, R., and Lu, J. (2012). Comparison of caspase-3 activation in tumor cells upon treatment of chemotherapeutic drugs using capillary electrophoresis. Protein Cell 3, 392–399.CrossRefGoogle Scholar
  36. van Horssen, R., Rens, J.A., Brunstein, F., Guns, V., van Gils, M., Hagen, T.L., and Eggermont, A.M. (2006). Intratumoural expression of TNF-R1 and EMAP-II in relation to response of patients treated with TNF-based isolated limb perfusion. Int J Cancer 119, 1481–1490.CrossRefGoogle Scholar
  37. Voron, T., Zinzindohoue, F., Journois, D., Herve, C., Ponzio, O., and Lucas, N. (2012). Hyperthermic isolated liver perfusion with melphalan and bevacizumab. J Visc Surg 150, 60–66.CrossRefGoogle Scholar
  38. Wang, D., Montgomery, R.B., Schmidt, L.J., Mostaghel, E.A., Huang, H., Nelson, P.S., and Tindall, D.J. (2009). Reduced tumor necrosis factor receptor-associated death domain expression is associated with prostate cancer progression. Cancer Res 69, 9448–9456.CrossRefGoogle Scholar
  39. Wood, L.J., Nail, L.M., Gilster, A., Winters, K.A., and Elsea, C.R. (2006a). Cancer chemotherapy-related symptoms: evidence to suggest a role for proinflammatory cytokines. Oncol Nurs Forum 33, 535–542.CrossRefGoogle Scholar
  40. Wood, L.J., Nail, L.M., Perrin, N.A., Elsea, C.R., Fischer, A., and Druker, B.J. (2006b). The cancer chemotherapy drug etoposide (VP-16) induces proinflammatory cytokine production and sickness behavior-like symptoms in a mouse model of cancer chemotherapy-related symptoms. Biol Res Nurs 8, 157–169.CrossRefGoogle Scholar
  41. Wu, X., Wei, H., Zhang, J., and Tian, Z. (2006). Increased uterine NKderived IFN-gamma and TNF-alpha in C57BL/6J mice during early gestation. Cell Mol Immunol 3, 131–137.Google Scholar
  42. Yoshimura, H., Dhar, D.K., Nakamoto, T., Kotoh, T., Takano, M., Soma, G., and Nagasue, N. (2003). Prognostic significance of tumor necrosis factor receptor in colorectal adenocarcinoma. Anticancer Res 23, 85–89.Google Scholar
  43. Zhao, X., Rong, L., Li, X., Liu, X., Deng, J., Wu, H., Xu, X., Erben, U., Wu, P., Syrbe, U., et al. (2012). TNF signaling drives myeloid-derived suppressor cell accumulation. J Clin Invest 122, 4094–4104.CrossRefGoogle Scholar

Copyright information

© Higher Education Press and Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Jingjing Deng
    • 1
    • 2
  • Xiaopu Zhao
    • 1
    • 2
  • Lijie Rong
    • 1
    • 2
  • Xiao Li
    • 1
  • Xiaoman Liu
    • 1
  • Zhihai Qin
    • 1
  1. 1.Key Laboratory of Protein and Peptide Pharmaceuticals; Chinese Academy of Sciences-University of Tokyo Joint Laboratory of Structural Virology and Immunology, Institute of BiophysicsChinese Academy of SciencesBeijingChina
  2. 2.University of Chinese Academy of SciencesBeijingChina

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