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Differential Expression of Intracellular Apoptotic Signaling Molecules in Tumor and Tumor-Infiltrating Lymphocytes During Development of Invasion and/or Metastasis of Gastric Carcinoma

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Abstract

The presence and functional status of intracellular expression of caspase 8, caspase 10, cFLIP, caspase 3, survivin, and NF-κB was investigated in permeabilized tumor and tumor-infiltrating lymphocytes (TIL) in gastric carcinoma (N = 20) from primary locus, metastatic gastric carcinoma (N = 22) from malignant ascites, and benign gastric mucosa (N = 20) for the control. The quantitative analysis was based on the percentage of positive cells by a flow cytometry. The results showed that the six intracellular molecules were constitutively expressed in primary and metastatic carcinomas as well as normal epithelium in nearly all the patients. In particular, metastatic carcinoma revealed to significantly overexpress these molecules. In the analysis of TIL, the expression of these six molecules could usually be observed in carcinoma and normal epithelium. There was aberrant expression of these molecules in immune TIL within metastatic carcinoma nests. Taken together, the results showed the significantly different expression of the signaling molecules in both tumor and TIL between primary and metastatic carcinoma nests. Increased expression of cFLIP, survivin, and NF-κB in carcinoma might play an important role in hindering an intracellular apoptotic process, followed by accelerating the cancer invasion and/or metastasis.

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References

  1. Nagata S: Apoptosis by death factor. Cell 88:355-365, 1997

    Google Scholar 

  2. Ashkenazi A, Dixit VM: Death receptors: signaling and modulation. Science 281:1305-1308, 1998

    Google Scholar 

  3. Muzio M, Chinnaiyan AM, Kischkel FC, O'Rourke K, Shevchenko A, Ni J, Scaffidi C, Bretz JD, Zhang M, Gentz R, Mann M, Krammaer PH, Peter ME, Dixit VM: FLICE, a novel FADD-homologous ICE/CED-3-like protease, is recruited to the CD95 (Fas/Apo-1) death-inducing signaling complex. Cell 85:817-827, 1996

    Google Scholar 

  4. Vincenz C, Dixit VM: Fas-associated death domain protein interleukin-1 beta-converting enzyme 2 (FLICE 2), an ICE/çed-3 homologue, is proximally involved in CD95-and p55-mediated death signaling. J Biol Chem 272:6578-6583, 1997

    Google Scholar 

  5. Cohen GM. Caspases: the executioners of apoptosis. Biochem J 326:1-16, 1997

    Google Scholar 

  6. Muzio M, Stockwell BR, Stennicke HR, Salvensen GS, Dixit VM: An induced proximity model for caspase-8 activation. J Biol Chem 273:2926-2930, 1998

    Google Scholar 

  7. Bodmer J-L, Holler N, Reynard S, Vinciguerra P, Schneider P, Juo P, Blenis J, Tschopp J: TRAIL receptor-2 signals apoptosis through FADD and caspase-8. Nature Cell Biol 2:241-243, 2000

    Google Scholar 

  8. Kuang AA, Diehl GE, Zhang J, Winoto A: FADD is required for DR4 and DR5-mediated apoptosis. J Biol Chem 275:25065-25068, 2000

    Google Scholar 

  9. Eggert A, Grotzer MA, Zuzak TJ, Wiewrodt BR, Ho R, Ikegami N, Brodeur GM: Resistance to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in neuroblastoma cells correlates with a loss of caspase-8 expression. Cancer Res 61:1314-1319, 2001

    Google Scholar 

  10. Wiley SR, Schooley K, Smolak PJ, Din WS, Huang CP, Nicholl JK, Sutherland GR, Davis Smith T, Rauch C, Smith CA, Goodwin RG: Identification and characterization of a new member of the TNF family that induces apoptosis. Immunity 3:673-682, 1995

    Google Scholar 

  11. Sheridan JP, Marsters SA, Pitti RM, GL, Gurney A, Skubatch A, Baldwin D, Ramakrishnan L, Gray CL, Baker K, Wood WI, Goddard AD, Godowski P, Ashkenazi A: Control of TRAIL-induced apoptosis by a family of signaling and decoy receptors. Science 277:818-821, 1997

    Google Scholar 

  12. Koyama S, Koike N, Adachi S: Fas receptor counterattack against tumor-infiltrating lymphocytes in vivo as a mechanism of immune escape by gastric carcinoma. J Cancer Res Clin Oncol 127:20-26, 2001

    Google Scholar 

  13. Koyama S, Koike N, Adachi S: Expression of TNF-related apoptosis inducing ligand (TRAIL) and its receptors in gastric carcinoma and tumor-infiltrating lymphocytes: a possible mechanism of immune evasion of the tumor. J Cancer Res Clin Oncol 128:73-79, 2002

    Google Scholar 

  14. Irmler M, Thome M, Hahne M, Schneider P, Hofmann K, Steiner V, Bodmer J-L, Schröter M, Burns K, Mattmann C, Rimoldi D, French LE, Tschopp T: Inhibition of death receptor signals by cellular FLIP. Nature 388:190-195, 1997

    Google Scholar 

  15. Hu S, Vincenz C, Ni J, Gentz R, Dixit VM: I-FLICE, a novel inhibitor of tumor necrosis factor receptor-1 and CD95-induced apoptosis. J Biol Chem 272:17255-17257, 1997

    Google Scholar 

  16. Ambrosini G, Adida C, Altieri DC: A novel anti-apoptosis gene, survivin, expressed in cancer and lymphoma. Nature Med 3:917-921, 1997

    Google Scholar 

  17. Tamm I, Wang Y, Sausville ED, Scudiero DA, Vigna N, Oltersdorf T, Reed JC: IAP-family protein survivin inhibits caspase activity and apoptosis induced by Fas (CD95), Bax, caspase, and anticancer drugs. Cancer Res 58:5315-5320, 1998

    Google Scholar 

  18. Lu C-D, Altieri DC, Tanigawa N: Expression of a novel antiapoptotic gene, survivin, correlated with tumor cell apoptosis and p53 accumulation in gastric carcinomas. Cancer Res 58:1808-1812, 1998

    Google Scholar 

  19. Okada E, Murai Y, Matsui K, Ishizawa S, Cheng C, Masuda M, Takano Y: Survivin expression in tumor cell nuclei of a favorable prognosis in gastric cancer patients. Cancer Lett 163:109-116, 2001

    Google Scholar 

  20. Krieg A, Mahotka C, Krieg T, Grabsch H, Müller W, Takeno S, Suschek CV, Heydthausen M, Gabbert HE, Gerharz CD: Expression of different survivin variants in gastric carcinomas: first clues to a role of survivin-2B in tumor progression. Br J Cancer 86:737-743, 2002

    Google Scholar 

  21. Baeuerle PA, Baltimore D: NF-κB: Ten years after. Cell 87:13-20, 1996

    Google Scholar 

  22. Wang C-Y, Mayo MW, Korneluk RG, Goeddel DV, Baldwin AS Jr NF-κB antiapoptosis: Induction of TRAF1 and TRAF2 and c-IAP1 and c-IAP2 suppress caspase-8 activation. Science 281:1680-1683, 1998

    Google Scholar 

  23. Huang S, DeGuzman A, Bucana CD, Fidler IJ: Nuclear factor-κB activity correlates with growth, angiogenesis, and metastasis of human melanoma cells in nude mice. Clin Cancer Res 6:2573-2581, 2000

    Google Scholar 

  24. Rayet B, Gélinas C: Aberrant rel/nfkb genes and activity in human cancer. Oncogene 18:6938-6947, 1999

    Google Scholar 

  25. Micheau O, Lens S, Gaide O, Alevizopoulos K, Tschopp J: NF-κB signals induce the expression of c-FLIP. Mol Cell Biol 21:5299-5305, 2001

    Google Scholar 

  26. Deveraux QL, Reed JC: IAP family proteins—suppressors of apoptosis. Genes Dev 13:239-252, 1999

    Google Scholar 

  27. Koyama S, Maruyama T, Adachi S, Nozue M: Expression of costimulatory molecules, B7-1 and B7-2 on human gastric carcinoma. J Cancer Res Clin Oncol 124:383-388, 1998

    Google Scholar 

  28. Koyama S, Maruyama T, Adachi S: Expression of epidermal growth factor receptor and CD44 splicing variants sharing exsons 6 and 9 on gastric and esophageal carcinomas: a two-color flow-cytometric analysis. J Cancer Res Clin Oncol 125:47-54, 1999

    Google Scholar 

  29. Koyama S: Apoptotic depletion of infiltrating mucosal lymphocytes associated with Fas ligand expression by Helicobacter pylori-infected gastric mucosal epithelium: human glandular stomach as a site of immune privilege. Dig Dis Sci 45:773-780, 2000

    Google Scholar 

  30. Koyama S: Flow cytometric measurement of tumor necrosis factor-related apoptosis inducing ligand and its receptors in gastric epithelium and infiltrating mucosal lymphocytes in Helicobacter pylori-associated gastritis. J Gastroenterol Hepatol 18:763-770, 2003

    Google Scholar 

  31. Japanese Research Society for Gastric Cancer. Japanese classification of gastric carcinoma, 2nd English ed. Gastric Cancer 1:10-24, 1998

  32. Tepper CG, Seldin M: Modulation of caspase-8 and FLICE-inhibitory protein expression as a potential mechanism of Epstein-Barr virus tumorigenesis in Burkitt's lymphoma. Blood 94:1727-1737, 1999

    Google Scholar 

  33. Griffith TS, Chin WA, Jackson GC, Lynch DH, Kubin MZ: Intracellular regulation of TRAIL-induced apoptosis in human melanoma cells. J Immunol 161:2833-2840, 1998

    Google Scholar 

  34. Leverkus M, Neumann M, Mengling T, Rauch CT, Bröcker E-B, Krammer PH, Walczak H: Regulation of tumor necrosis factor-related apoptosis-inducing ligand sensitivity in primary and transformed human keratinocytes. Cancer Res 60:553-559, 2000

    Google Scholar 

  35. Medema JP, de Jong J, van Hall T, Melief CJM, Offringa R: Immune escape of tumors in vivo by expression of cellular FLICE-inhibitory protein. J Exp Med 190:1033-1038, 1999

    Google Scholar 

  36. Gilmore T, Gapuzan M-E, Kalaitzidis D, Starczynowski D: Rel/NF-κB/IκB signal transduction in the generation and treatment of human cancer. Cancer Lett 181:1-9, 2002

    Google Scholar 

  37. Sasaki N, Morisaki T, Hashizume K, Yao T, Tsuneyoshi M, Noshiro H, Nakamura K, Yamanaka T, Uchiyama A, Tanaka M, Katano M: Nuclear factor-κB p65 (ReIA) transcription factor is constitutively activated in human gastric carcinoma tissue. Clin Cancer Res 7:4136-4142, 2001

    Google Scholar 

  38. Franco AV, Zhang XD, Berkel EV, Sanders JE, Zhang XY, Thomas WD, Nguyen T, Hersey P: The role NF-κB in TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis of melanoma cells. J Immunol 166:5337-5345, 2001

    Google Scholar 

  39. Trauzold A, Wermann H, Arlt A, Schütze S, Schäfer H, Oestern S, Röder C, Ungefroren H, Lampe E, Heinrich M, Walczak H, Kalthroff H: CD95 and TRAIL receptor-mediated activation of protein kinase C and NF-κB contributes to apoptosis resistance in ductal pancreatic adenocarcinoma cells. Oncogene 20:4258-4269, 2001

    Google Scholar 

  40. Oya M, Ohtsubo M, Takayanagi A, Tachibana M, Shimizu N, Murai M: Constitutive activation of nuclear factor-κB prevents TRAIL-induced apoptosis in renal cancer cells. Oncogene 20:3888-3896, 2001

    Google Scholar 

  41. Huang S, Pettaway CA, Uehara H, Bucana CD, Fidler IJ: Blockade of NF-κB activity in human prostate cancer cell lines is associated with suppression of angiogenesis, invasion, and metastasis. Oncogene 20:4188-4197, 2001

    Google Scholar 

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Correspondence to Shohei Koyama.

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Koyama, S. Differential Expression of Intracellular Apoptotic Signaling Molecules in Tumor and Tumor-Infiltrating Lymphocytes During Development of Invasion and/or Metastasis of Gastric Carcinoma. Dig Dis Sci 48, 2290–2300 (2003). https://doi.org/10.1023/B:DDAS.0000007865.96569.9a

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  • DOI: https://doi.org/10.1023/B:DDAS.0000007865.96569.9a

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