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. 1998 Jan;152(1):93–100.

Expression of interleukin-8 correlates with vascularity in human gastric carcinomas.

Y Kitadai 1, K Haruma 1, K Sumii 1, S Yamamoto 1, T Ue 1, H Yokozaki 1, W Yasui 1, Y Ohmoto 1, G Kajiyama 1, I J Fidler 1, E Tahara 1
PMCID: PMC1858127  PMID: 9422527

Abstract

Interleukin (IL)-8 is a multifunctional cytokine that can stimulate the division of endothelial cells. We examined the expression of IL-8 mRNA using Northern blot analysis and in situ mRNA hybridization (ISH) and protein production using enzyme-linked immunosorbent assay and immunohistochemistry in 8 human gastric carcinoma cell lines and 39 gastric carcinomas and corresponding normal mucosa (34 surgical specimens and 5 biopsy specimens). Of the 8 human gastric carcinoma cell lines, 6 expressed 1.8-kb IL-8 mRNA and secreted various levels of IL-8 protein. The expression of IL-8 by TMK-1 cells was induced by exposure to IL-1 alpha, epidermal growth factor, and transforming growth factor-alpha, shown previously to be autocrine growth stimulators for human gastric carcinoma cells. In tumor tissues, most of the tumors (28 of 34 surgical specimens and 4 of 5 biopsy specimens) expressed IL-8 at higher levels than the corresponding normal mucosa. ISH and immunohistochemical analyses revealed that IL-8 mRNA and protein were localized in the cytoplasm of tumor cells. The number of blood vessels in the gastric carcinomas was determined by using antibodies against CD34. The level of IL-8 mRNA in the neoplasms strongly correlated with vascularization (Spearman correlation, r = 0.812; P = 0.001). The data suggest that IL-8 produced by tumor cells may regulate neovascularization and, hence, the growth and spread of human gastric carcinoma.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Aihara M., Tsuchimoto D., Takizawa H., Azuma A., Wakebe H., Ohmoto Y., Imagawa K., Kikuchi M., Mukaida N., Matsushima K. Mechanisms involved in Helicobacter pylori-induced interleukin-8 production by a gastric cancer cell line, MKN45. Infect Immun. 1997 Aug;65(8):3218–3224. doi: 10.1128/iai.65.8.3218-3224.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Arenberg D. A., Kunkel S. L., Polverini P. J., Glass M., Burdick M. D., Strieter R. M. Inhibition of interleukin-8 reduces tumorigenesis of human non-small cell lung cancer in SCID mice. J Clin Invest. 1996 Jun 15;97(12):2792–2802. doi: 10.1172/JCI118734. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bucana C. D., Radinsky R., Dong Z., Sanchez R., Brigati D. J., Fidler I. J. A rapid colorimetric in situ mRNA hybridization technique using hyperbiotinylated oligonucleotide probes for analysis of mdr1 in mouse colon carcinoma cells. J Histochem Cytochem. 1993 Apr;41(4):499–506. doi: 10.1177/41.4.8095509. [DOI] [PubMed] [Google Scholar]
  4. Crabtree J. E., Peichl P., Wyatt J. I., Stachl U., Lindley I. J. Gastric interleukin-8 and IgA IL-8 autoantibodies in Helicobacter pylori infection. Scand J Immunol. 1993 Jan;37(1):65–70. doi: 10.1111/j.1365-3083.1993.tb01666.x. [DOI] [PubMed] [Google Scholar]
  5. DeMarco D., Kunkel S. L., Strieter R. M., Basha M., Zurier R. B. Interleukin-1 induced gene expression of neutrophil activating protein (interleukin-8) and monocyte chemotactic peptide in human synovial cells. Biochem Biophys Res Commun. 1991 Jan 31;174(2):411–416. doi: 10.1016/0006-291x(91)91431-b. [DOI] [PubMed] [Google Scholar]
  6. Fan D., Bucana C. D., O'Brian C. A., Zwelling L. A., Seid C., Fidler I. J. Enhancement of murine tumor cell sensitivity to adriamycin by presentation of the drug in phosphatidylcholine-phosphatidylserine liposomes. Cancer Res. 1990 Jun 15;50(12):3619–3626. [PubMed] [Google Scholar]
  7. Feinberg A. P., Vogelstein B. A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity. Anal Biochem. 1983 Jul 1;132(1):6–13. doi: 10.1016/0003-2697(83)90418-9. [DOI] [PubMed] [Google Scholar]
  8. Fidler I. J. Critical factors in the biology of human cancer metastasis: twenty-eighth G.H.A. Clowes memorial award lecture. Cancer Res. 1990 Oct 1;50(19):6130–6138. [PubMed] [Google Scholar]
  9. Folkman J. How is blood vessel growth regulated in normal and neoplastic tissue? G.H.A. Clowes memorial Award lecture. Cancer Res. 1986 Feb;46(2):467–473. [PubMed] [Google Scholar]
  10. Folkman J. What is the evidence that tumors are angiogenesis dependent? J Natl Cancer Inst. 1990 Jan 3;82(1):4–6. doi: 10.1093/jnci/82.1.4. [DOI] [PubMed] [Google Scholar]
  11. Forman D., Newell D. G., Fullerton F., Yarnell J. W., Stacey A. R., Wald N., Sitas F. Association between infection with Helicobacter pylori and risk of gastric cancer: evidence from a prospective investigation. BMJ. 1991 Jun 1;302(6788):1302–1305. doi: 10.1136/bmj.302.6788.1302. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Greene G. F., Kitadai Y., Pettaway C. A., von Eschenbach A. C., Bucana C. D., Fidler I. J. Correlation of metastasis-related gene expression with metastatic potential in human prostate carcinoma cells implanted in nude mice using an in situ messenger RNA hybridization technique. Am J Pathol. 1997 May;150(5):1571–1582. [PMC free article] [PubMed] [Google Scholar]
  13. Gutman M., Singh R. K., Xie K., Bucana C. D., Fidler I. J. Regulation of interleukin-8 expression in human melanoma cells by the organ environment. Cancer Res. 1995 Jun 1;55(11):2470–2475. [PubMed] [Google Scholar]
  14. Ito R., Kitadai Y., Kyo E., Yokozaki H., Yasui W., Yamashita U., Nikai H., Tahara E. Interleukin 1 alpha acts as an autocrine growth stimulator for human gastric carcinoma cells. Cancer Res. 1993 Sep 1;53(17):4102–4106. [PubMed] [Google Scholar]
  15. Kita M., Ohmoto Y., Hirai Y., Yamaguchi N., Imanishi J. Induction of cytokines in human peripheral blood mononuclear cells by mycoplasmas. Microbiol Immunol. 1992;36(5):507–516. doi: 10.1111/j.1348-0421.1992.tb02048.x. [DOI] [PubMed] [Google Scholar]
  16. Kitadai Y., Yasui W., Yokozaki H., Kuniyasu H., Ayhan A., Haruma K., Kajiyama G., Johnson G. R., Tahara E. Expression of amphiregulin, a novel gene of the epidermal growth factor family, in human gastric carcinomas. Jpn J Cancer Res. 1993 Aug;84(8):879–884. doi: 10.1111/j.1349-7006.1993.tb02061.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Koch A. E., Polverini P. J., Kunkel S. L., Harlow L. A., DiPietro L. A., Elner V. M., Elner S. G., Strieter R. M. Interleukin-8 as a macrophage-derived mediator of angiogenesis. Science. 1992 Dec 11;258(5089):1798–1801. doi: 10.1126/science.1281554. [DOI] [PubMed] [Google Scholar]
  18. Kuniyasu H., Yoshida K., Yokozaki H., Yasui W., Ito H., Toge T., Ciardiello F., Persico M. G., Saeki T., Salomon D. S. Expression of cripto, a novel gene of the epidermal growth factor family, in human gastrointestinal carcinomas. Jpn J Cancer Res. 1991 Sep;82(9):969–973. doi: 10.1111/j.1349-7006.1991.tb01929.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Macchiarini P., Fontanini G., Hardin M. J., Squartini F., Angeletti C. A. Relation of neovascularisation to metastasis of non-small-cell lung cancer. Lancet. 1992 Jul 18;340(8812):145–146. doi: 10.1016/0140-6736(92)93217-b. [DOI] [PubMed] [Google Scholar]
  20. Matsushima K., Baldwin E. T., Mukaida N. Interleukin-8 and MCAF: novel leukocyte recruitment and activating cytokines. Chem Immunol. 1992;51:236–265. [PubMed] [Google Scholar]
  21. Matsushima K., Morishita K., Yoshimura T., Lavu S., Kobayashi Y., Lew W., Appella E., Kung H. F., Leonard E. J., Oppenheim J. J. Molecular cloning of a human monocyte-derived neutrophil chemotactic factor (MDNCF) and the induction of MDNCF mRNA by interleukin 1 and tumor necrosis factor. J Exp Med. 1988 Jun 1;167(6):1883–1893. doi: 10.1084/jem.167.6.1883. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Ochiai A., Yasui W., Tahara E. Growth-promoting effect of gastrin on human gastric carcinoma cell line TMK-1. Jpn J Cancer Res. 1985 Nov;76(11):1064–1071. [PubMed] [Google Scholar]
  23. Parsonnet J., Friedman G. D., Vandersteen D. P., Chang Y., Vogelman J. H., Orentreich N., Sibley R. K. Helicobacter pylori infection and the risk of gastric carcinoma. N Engl J Med. 1991 Oct 17;325(16):1127–1131. doi: 10.1056/NEJM199110173251603. [DOI] [PubMed] [Google Scholar]
  24. Radinsky R., Bucana C. D., Ellis L. M., Sanchez R., Cleary K. R., Brigati D. J., Fidler I. J. A rapid colorimetric in situ messenger RNA hybridization technique for analysis of epidermal growth factor receptor in paraffin-embedded surgical specimens of human colon carcinomas. Cancer Res. 1993 Mar 1;53(5):937–943. [PubMed] [Google Scholar]
  25. Radinsky R., Kraemer P. M., Raines M. A., Kung H. J., Culp L. A. Amplification and rearrangement of the Kirsten ras oncogene in virus-transformed BALB/c 3T3 cells during malignant tumor progression. Proc Natl Acad Sci U S A. 1987 Aug;84(15):5143–5147. doi: 10.1073/pnas.84.15.5143. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Reed J. A., Manahan L. J., Park C. S., Brigati D. J. Complete one-hour immunocytochemistry based on capillary action. Biotechniques. 1992 Sep;13(3):434–443. [PubMed] [Google Scholar]
  27. Schadendorf D., Möller A., Algermissen B., Worm M., Sticherling M., Czarnetzki B. M. IL-8 produced by human malignant melanoma cells in vitro is an essential autocrine growth factor. J Immunol. 1993 Sep 1;151(5):2667–2675. [PubMed] [Google Scholar]
  28. Schröder J. M., Christophers E. Identification of C5ades arg and an anionic neutrophil-activating peptide (ANAP) in psoriatic scales. J Invest Dermatol. 1986 Jul;87(1):53–58. doi: 10.1111/1523-1747.ep12523566. [DOI] [PubMed] [Google Scholar]
  29. Singh R. K., Gutman M., Radinsky R., Bucana C. D., Fidler I. J. Expression of interleukin 8 correlates with the metastatic potential of human melanoma cells in nude mice. Cancer Res. 1994 Jun 15;54(12):3242–3247. [PubMed] [Google Scholar]
  30. Smith-McCune K. K., Weidner N. Demonstration and characterization of the angiogenic properties of cervical dysplasia. Cancer Res. 1994 Feb 1;54(3):800–804. [PubMed] [Google Scholar]
  31. Smith D. R., Polverini P. J., Kunkel S. L., Orringer M. B., Whyte R. I., Burdick M. D., Wilke C. A., Strieter R. M. Inhibition of interleukin 8 attenuates angiogenesis in bronchogenic carcinoma. J Exp Med. 1994 May 1;179(5):1409–1415. doi: 10.1084/jem.179.5.1409. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Strieter R. M., Kunkel S. L., Elner V. M., Martonyi C. L., Koch A. E., Polverini P. J., Elner S. G. Interleukin-8. A corneal factor that induces neovascularization. Am J Pathol. 1992 Dec;141(6):1279–1284. [PMC free article] [PubMed] [Google Scholar]
  33. Strieter R. M., Polverini P. J., Arenberg D. A., Walz A., Opdenakker G., Van Damme J., Kunkel S. L. Role of C-X-C chemokines as regulators of angiogenesis in lung cancer. J Leukoc Biol. 1995 May;57(5):752–762. doi: 10.1002/jlb.57.5.752. [DOI] [PubMed] [Google Scholar]
  34. Tachibana M., Miyakawa A., Nakashima J., Murai M., Nakamura K., Kubo A., Hata J. I. Constitutive production of multiple cytokines and a human chorionic gonadotrophin beta-subunit by a human bladder cancer cell line (KU-19-19): possible demonstration of totipotential differentiation. Br J Cancer. 1997;76(2):163–174. doi: 10.1038/bjc.1997.358. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Tahara E. Growth factors and oncogenes in human gastrointestinal carcinomas. J Cancer Res Clin Oncol. 1990;116(2):121–131. doi: 10.1007/BF01612665. [DOI] [PubMed] [Google Scholar]
  36. Tahara E. Molecular mechanism of stomach carcinogenesis. J Cancer Res Clin Oncol. 1993;119(5):265–272. doi: 10.1007/BF01212724. [DOI] [PubMed] [Google Scholar]
  37. Takahashi Y., Cleary K. R., Mai M., Kitadai Y., Bucana C. D., Ellis L. M. Significance of vessel count and vascular endothelial growth factor and its receptor (KDR) in intestinal-type gastric cancer. Clin Cancer Res. 1996 Oct;2(10):1679–1684. [PubMed] [Google Scholar]
  38. Takahashi Y., Kitadai Y., Bucana C. D., Cleary K. R., Ellis L. M. Expression of vascular endothelial growth factor and its receptor, KDR, correlates with vascularity, metastasis, and proliferation of human colon cancer. Cancer Res. 1995 Sep 15;55(18):3964–3968. [PubMed] [Google Scholar]
  39. Talley N. J., Zinsmeister A. R., Weaver A., DiMagno E. P., Carpenter H. A., Perez-Perez G. I., Blaser M. J. Gastric adenocarcinoma and Helicobacter pylori infection. J Natl Cancer Inst. 1991 Dec 4;83(23):1734–1739. doi: 10.1093/jnci/83.23.1734. [DOI] [PubMed] [Google Scholar]
  40. Tanimoto H., Yoshida K., Yokozaki H., Yasui W., Nakayama H., Ito H., Ohama K., Tahara E. Expression of basic fibroblast growth factor in human gastric carcinomas. Virchows Arch B Cell Pathol Incl Mol Pathol. 1991;61(4):263–267. doi: 10.1007/BF02890427. [DOI] [PubMed] [Google Scholar]
  41. Uemura N., Mukai T., Okamoto S., Yamaguchi S., Mashiba H., Taniyama K., Sasaki N., Haruma K., Sumii K., Kajiyama G. Effect of Helicobacter pylori eradication on subsequent development of cancer after endoscopic resection of early gastric cancer. Cancer Epidemiol Biomarkers Prev. 1997 Aug;6(8):639–642. [PubMed] [Google Scholar]
  42. Wang J. M., Taraboletti G., Matsushima K., Van Damme J., Mantovani A. Induction of haptotactic migration of melanoma cells by neutrophil activating protein/interleukin-8. Biochem Biophys Res Commun. 1990 May 31;169(1):165–170. doi: 10.1016/0006-291x(90)91449-3. [DOI] [PubMed] [Google Scholar]
  43. Weidner N., Carroll P. R., Flax J., Blumenfeld W., Folkman J. Tumor angiogenesis correlates with metastasis in invasive prostate carcinoma. Am J Pathol. 1993 Aug;143(2):401–409. [PMC free article] [PubMed] [Google Scholar]
  44. Weidner N., Semple J. P., Welch W. R., Folkman J. Tumor angiogenesis and metastasis--correlation in invasive breast carcinoma. N Engl J Med. 1991 Jan 3;324(1):1–8. doi: 10.1056/NEJM199101033240101. [DOI] [PubMed] [Google Scholar]
  45. Yanagihara K., Seyama T., Tsumuraya M., Kamada N., Yokoro K. Establishment and characterization of human signet ring cell gastric carcinoma cell lines with amplification of the c-myc oncogene. Cancer Res. 1991 Jan 1;51(1):381–386. [PubMed] [Google Scholar]
  46. Yoshida K., Kyo E., Tsujino T., Sano T., Niimoto M., Tahara E. Expression of epidermal growth factor, transforming growth factor-alpha and their receptor genes in human gastric carcinomas; implication for autocrine growth. Jpn J Cancer Res. 1990 Jan;81(1):43–51. doi: 10.1111/j.1349-7006.1990.tb02505.x. [DOI] [PMC free article] [PubMed] [Google Scholar]

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