Abstract
Lymph node metastasis is one of the prognostic factors in gastric cancer. We have previously reported that decreased intercellular adhesion molecule‐1 (ICAM‐1) expression on cancer cells is associated with lymph node metastasis using a gastric cancer cell. In this study, we transfected ICAM‐1 gene into a gastric cancer cell line, 2MLN, and analyzed the effect on lymph node metastasis in vitro and in vivo. A significantly greater amount of peripheral blood mononuclear cells (PBMC) adhered to ICAM‐1 transfected 2MLN cells, 2MLN/ICAM cells, than to 2MLN/Vector cells. The lysis of 2MLN/ICAM cells by PBMC was significantly increased compared with that of 2MLN/Vector cells. The tumor growth rate of 2MLN/ICAM cells was significantly decreased in vivo. Lymph node metastases caused by 2MLN/ICAM cells were recognized as being fewer in number and smaller, while many lymph node metastases were caused by 2MLN cells. Histologic findings showed that leukocytes were heavily infiltrated in both the 2MLN/ICAM tumors and metastatic lesions, while only a few leukocytes were observed in the lesions associated with 2MLN cells. The above findings indicate that ICAM‐1 gene transduction could prove to be an effective gene therapy for lymph node metastasis of gastric cancer.
Keywords: ICAM‐1, Lymph node metastasis, Gene therapy, Gastric cancer
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REFERENCES
- 1. ) Maruyama , K. , Okabayashi , K. and Kinoshita , T.Progress in gastric cancer surgery in Japan and its limits of radicality . World J. Surg. , 11 , 418 – 425 ( 1987. ). [DOI] [PubMed] [Google Scholar]
- 2. ) Soga , J. , Ohyama , S. , Miyashita , K. , Suzuki , T. , Nashimoto , A. , Tanaka , O. , Sasaki , K. and Muto , T.A statistical evaluation of advancement in gastric cancer surgery with special reference to the significance of lymphadenectomy for cure . World J. Surg. , 12 , 398 – 405 ( 1988. ). [DOI] [PubMed] [Google Scholar]
- 3. ) Maehara , Y. , Emi , Y. , Baba , H. , Adachi , Y. , Akazawa , K. , Ichiyoshi , Y. and Sugimachi , K.Recurrences and related characteristics of gastric cancer . Br. J. Cancer , 74 , 975 – 979 ( 1996. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4. ) Siewert , J. R. , Bottcher , K. , Roder , J. D. , Busch , R. , Hermanek , P. and Meyer , H. J.Prognostic relevance of systematic lymph node dissection in gastric carcinoma . Br. J. Surg. , 80 , 1015 – 1018 ( 1993. ). [DOI] [PubMed] [Google Scholar]
- 5. ) de Manzoni , G. , Verlato , G. , Guglielmi , A. , Laterza , E. , Genna , M. and Cordiano , C.Prognostic significance of lymph node dissection in gastric cancer . Br. J. Surg. , 83 , 1604 – 1607 ( 1996. ). [DOI] [PubMed] [Google Scholar]
- 6. ) Fidler , I. J.Critical factors in the biology of human cancer metastasis . Cancer Res. , 50 , 6130 – 6138 ( 1990. ). [PubMed] [Google Scholar]
- 7. ) Roos , E.Cellular adhesion, invasion and metastasis . Biochim. Biophys. Acta , 738 , 263 – 284 ( 1984. ). [DOI] [PubMed] [Google Scholar]
- 8. ) Nicolson , G. L.Cancer metastasis: tumor cell and host organ properties important in metastasis to specific secondary sites . Biochim. Biophys. Acta , 948 , 175 – 224 ( 1988. ). [DOI] [PubMed] [Google Scholar]
- 9. ) Oka , H. , Shiozaki , H. , Kobayashi , K. , Inoue , M. , Tahara , H. , Kobayashi , T. , Takatsuka , Y. , Matsuyoshi , N. , Hirano , S. , Takeichi , M. and Takesada , M.Expression of E‐cadherin cell adhesion molecules in human breast cancer tissues and its relationship to metastasis . Cancer Res. , 53 , 1696 – 1701 ( 1993. ). [PubMed] [Google Scholar]
- 10. ) Doki , Y. , Shiozaki , H. , Tahara , H. , Inoue , M. , Oka , H. , Iihara , K. , Kadowaki , T. , Takeichi , M. and Mori , T.Correlation between E‐cadherin expression and invasiveness in vitro in a human esophageal cancer cell line . Cancer Res. , 53 , 3421 – 3426 ( 1993. ). [PubMed] [Google Scholar]
- 11. ) Shino , Y. , Watanabe , A. , Yamada , Y. , Tanase , M. , Yamada , T. , Matsuda , M. , Yamashita , J. , Tatsumi , M. , Miwa , M. and Nakao , T.Clinicopathologic evaluation of immunohistochemical E‐cadherin expression in human gastric carcinomas . Cancer , 76 , 2193 – 2201 ( 1995. ). [DOI] [PubMed] [Google Scholar]
- 12. ) Melief , C. J.Tumor eradication by adoptive transfer of cytotoxic T lymphocytes . Adv. Cancer Res. , 58 , 143 – 175 ( 1992. ). [DOI] [PubMed] [Google Scholar]
- 13. ) Herberman , R. B. and Ortaldo , J. R.Natural killer cells: their roles in defenses against disease . Science , 214 , 24 – 30 ( 1981. ). [DOI] [PubMed] [Google Scholar]
- 14. ) Schmidt , R. E. , Bartley , G. , Levine , H. , Schlossman , S. F. and Ritz , J.Functional characterization of LFA‐1 antigens in the interaction of human NK clones and target cells . J. Immunol. , 135 , 1020 – 1025 ( 1985. ). [PubMed] [Google Scholar]
- 15. ) Bretscher , P. and Cohn , M.A theory of self‐nonself discrimination . Science , 169 , 1042 – 1049 ( 1970. ). [DOI] [PubMed] [Google Scholar]
- 16. ) Lafferty , K. J. , Prowse , S. J. , Simeonovic , C. J. and Warren , H. S.Immunobiology of tissue transplantation: a return to the passenger leukocyte concept . Annu. Rev. Immunol. , 1 , 143 – 173 ( 1983. ). [DOI] [PubMed] [Google Scholar]
- 17. ) Mueller , D. L. , Jenkins , M. K. and Schwartz , R. H.Clonal expansion versus functional clonal inactivation: a costimulatory signalling pathway determines the outcome of T cell antigen receptor occupancy . Annu. Rev. Immunol. , 7 , 445 – 480 ( 1989. ). [DOI] [PubMed] [Google Scholar]
- 18. ) Van Seventer , G. A. , Shimizu , Y. , Horgan , K. J. and Shaw , S.The LFA‐1 ligand ICAM‐1 provides an important costimulatory signal for T cell receptor‐mediated activation of resting T cells . J. Immunol. , 144 , 4579 – 4586 ( 1990. ). [PubMed] [Google Scholar]
- 19. ) Passlick , B. , Pantel , K. , Kubuschok , B. , Angstwurm , M. , Neher , A. , Thetter , O. , Schweiberer , L. and Izbicki , J. R.Expression of MHC molecules and ICAM‐1 on non‐small cell lung carcinomas: association with early lymphatic spread of tumour cells . Eur. J. Cancer , 32 , 141 – 145 ( 1996. ). [DOI] [PubMed] [Google Scholar]
- 20. ) Hosch , S. B. , Izbicki , J. R. , Pichlmeier , U. , Stoecklein , N. , Niendorf , A. , Knoefel , W. T. , Broelsch , C. E. and Pantel , K.Expression and prognostic significance of immunoregulatory molecules in esophageal cancer . Int. J. Cancer , 74 , 582 – 587 ( 1997. ). [DOI] [PubMed] [Google Scholar]
- 21. ) Shibata , M. , Ando , K. , Amano , S. and Kurosu , Y.Local expression and circulating form of ICAM‐1 in colorectal cancer . Ann. Cancer Res. Ther. , 5 , 29 – 33 ( 1996. ). [Google Scholar]
- 22. ) Ogawa , Y. , Hirakawa , K. , Nakata , B. , Fujihara , T. , Sawada , T. , Kato , Y. , Yoshikawa , K. and Sowa , M.Expression of intercellular adhesion molecule‐1 in invasive breast cancer reflects low growth potential, negative lymph node involvement, and good prognosis . Clin. Cancer Res. , 4 , 31 – 36 ( 1998. ). [PubMed] [Google Scholar]
- 23. ) Fujihara , T. , Sawada , T. , Hirakawa , K. , Chung , Y. S. , Yashiro , M. , Inoue , T. and Sowa , M.Establishment of lymph node metastatic model for human gastric cancer in nude mice and analysis of factors associated with metastasis . Clin. Exp. Metastasis , 16 , 389 – 398 ( 1998. ). [DOI] [PubMed] [Google Scholar]
- 24. ) Tanaka , Y. , Albelda , S. M. , Horgan , K. J. , van Seventer , G. A. , Shimizu , Y. , Newman , W. , Hallam , J. , Newman , P. J. , Buck , C. A. and Shaw , S.CD31 expressed on distinctive T cell subsets is a preferential amplifier of beta 1 integrinmediated adhesion . J. Exp. Med. , 176 , 245 – 253 ( 1992. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25. ) Shimizu , Y. , Newman , W. , Gopal , T. V. , Horgan , K. J. , Graber , N. , Beall , L. D. , van Seventer , G. A. and Shaw , S.Four molecular pathways of T cell adhesion to endothelial cells: roles of LFA‐1, VCAM‐1, and ELAM‐1 and changes in pathway hierarchy under different activation conditions . J. Cell Biol. , 113 , 1203 – 1212 ( 1991. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26. ) Kasai , M. , Yoneda , T. , Habu , S. , Maruyama , Y. , Okumura , K. and Tokunaga , T.In vivo effect of anti‐asialo GM1 antibody on natural killer activity . Nature , 291 , 334 – 335 ( 1981. ). [DOI] [PubMed] [Google Scholar]
- 27. ) Kohl , S. , Springer , T. A. , Schmalstieg , F. C. , Loo , L. S. and Anderson , D. C.Defective natural killer cytotoxicity and polymorphonuclear leukocyte antibody‐dependent cellular cytotoxicity in patients with LFA‐1/OKM‐1 deficiency . J. Immunol. , 133 , 2972 – 2978 ( 1984. ). [PubMed] [Google Scholar]
- 28. ) Timonen , T. , Patarroyo , M. and Gahmberg , C. G.CD11ac/CD18 and GP84 (LB‐2) adhesion molecules on human large granular lymphocytes and their participation in natural killing . J. Immunol. , 141 , 1041 – 1046 ( 1988. ). [PubMed] [Google Scholar]
- 29. ) Jonjic , N. , Alberti , S. , Bernasconi , S. , Peri , G. , Jilek , P. , Anichini , A. , Parmiani , G. and Mantovani , A.Heterogeneous susceptibility of human melanoma clones to monocyte cytotoxicity: role of ICAM‐1 defined by antibody blocking and gene transfer . Eur. J. Immunol. , 22 , 2255 – 2260 ( 1992. ). [DOI] [PubMed] [Google Scholar]
- 30. ) Van Seventer , G. A. , Shimizu , Y. , Horgan , K. J. and Shaw , S.The LFA‐1 ligand ICAM‐1 provides an important costimulatory signal for T cell receptor‐mediated activation of resting T cells . J. Immunol. , 144 , 4579 – 4586 ( 1990. ). [PubMed] [Google Scholar]
- 31. ) Xu , H. , Tong , I. , DeFougerolles , A. and Springer , T.Isolation, characterization and expression of mouse ICAM‐2 complimentary and genomic DNA . J. Immunol. , 149 , 2650 – 2655 ( 1992. ). [PubMed] [Google Scholar]
- 32. ) Burno , D. K. , Kyprianou , N. , Sartor , W. M. , Fabian , D. F. , Turner , J. , Vu , T. , Patel , A. , Trimbach , C. and Lefor , A. T.Transfection of a murine fibrosarcoma with intercellular adhesion molecule‐1 enhances the response to adoptive immunotherapy . Surgery , 118 , 237 – 244 ( 1995. ). [DOI] [PubMed] [Google Scholar]