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Inhibition of cancer cell motility and invasion by interleukin-12

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Tumour cell motility and attachment are crucial requirements in the formation of metastatic lesions. These properties are affected by a number of cytokines including hepatocyte growth factor/scatter factor (HGF/SF) and several immunoregulatory proteins, including interleukin-12 (IL-12). Although IL-12 has been reported to exhibit potent anti-tumour effects in vivo, a direct effect of IL-12 on cancer cells has not been reported. We show here that IL-12 directly inhibited the attachment of the human colon cancer cell lines HRT18, HT29 and HT115 to Matrigel, HGF/SF-stimulated cell motility and HGF/SF-induced cell invasion through a reconstituted basement membrane. IL-12 did not affect the growth of these cell lines. Flow cytometry, Western analysis and immunohistochemistry revealed an up-regulation of E-cadherin cell-surface adhesion molecules. These direct effects of IL-12 on colon cancer cells suggest a potentially important role for IL-12 in metastasis.

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References

  1. Liotta LA, 1987, Biochemical mechanisms of tumour invasion and metastasis. Clin Physiol Biochem, 5, 190–99.

    Google Scholar 

  2. Schiffmann E, 1990, Motility as a principal requirement for metastasis. Cancer Invest, 8, 673–4.

    Google Scholar 

  3. Hart IR, Goode, NT and Wilson RE, 1989, Molecular aspects of the metastatic cascade. Biochim Biophys Acta, 989, 65–84.

    Google Scholar 

  4. Liotta LA and Stracke ML, 1988, Tumour invasion and metastasis: biochemical mechanisms. Cancer Treat Res, 40, 223–8.

    Google Scholar 

  5. Fidler IJ, Gersten DM and Hart IR, 1978, The biology of cancer invasion and metastasis. Adv Cancer Res, 28, 149–205.

    Google Scholar 

  6. Takeichi M, 1988, The cadherins: cell-cell adhesion molecules controlling animal morphogenesis. Development, 102, 639–55.

    CAS  PubMed  Google Scholar 

  7. Takeichi M, 1991, Cadherin cell adhesion receptors as a morphogenetic regulator. Science, 251, 1451–5.

    Google Scholar 

  8. Shiozaki H, Kobayashi K, Inoue M, et al. 1993, Expression of e-cadherin cell adhesion molecules in human breast cancer tissues and its relationship to metastasis. Cancer Res, 53, 1696–701.

    Google Scholar 

  9. Doki Y, Shiozaki H, Tahara H, et al. 1993, Correlation between e-cadherin expression and invasiveness in vitro in a human oesophageal cancer cell line. Cancer Res, 53, 3421–6.

    Google Scholar 

  10. Mayer B, Johnson JP, Leitl F, et al. 1993, e-cadherin expression in primary and metastatic gastric cancer: down-regulation correlates with cellular dedifferentiation and glandular disintegration. Cancer Res, 53, 1690–5.

    Google Scholar 

  11. Umbas R, Schlaken JA, Aalders, TW, et al. 1992, Expression of the cellular adhesion molecule e-cadherin is reduced or absent in high-grade prostate cancer. Cancer Res, 52, 5104–9.

    Google Scholar 

  12. Shiozaki H, Tahara H, Oka H, et al. 1991, Expression of immunoreactive e-cadherin adhesion molecules in human cancers. Am J Pathol, 139, 17–23.

    Google Scholar 

  13. Bongiorno PF, Kasspooles MAl-, et al. 1995, e-cadherin expression in primary and metastatic thoracic neoplasms and in Barrett's oesophagus. Br J Cancer, 71, 166–72.

    Google Scholar 

  14. Brunda MJ, Luistro L, Warrier RR, et al. 1993, Antitumour and antimetastatic activity of interleukin-12 against murine tumours. J Exp Med, 178, 1223–30.

    Google Scholar 

  15. Truitt GA, Bontempo JW, Stern LL, et al. 1989, Efficacy and toxicology elicited by recombinant interferons alpha and gamma when administered in combination to tumour-bearing mice. Biotechnol Ther, 1, 1–8.

    Google Scholar 

  16. Kobayashi M, Fitz L, Ryan M, et al. 1989, Identification and purification of natural killer cell stimulatory factor (NKSF), a cytokine with multiple biological effects on human lymphocytes. J Exp Med, 170, 827–45.

    Google Scholar 

  17. Stern AS, Podalski FJ, Hulmes JD, et al. 1990, Purification to homogeneity and partial characterisation of cytotoxic lymphocyte maturation factor from human B-lymphoblastoid cells. Proc Natl Acad Sci USA, 87, 6808–12.

    Google Scholar 

  18. D'Andrea A, Rengaraju M, Valiante NM, et al. 1992, Production of natural killer cell stimulatory factor (NKSF/IL-12) by peripheral blood mononuclear cells. J Exp Med, 176, 1387–98.

    Google Scholar 

  19. Gatley MK, Desai BB, Wolitzki AG, et al. 1991, Regulation of human lymphocyte proliferation by a heterodimeric cytokine, IL-12 (cytotoxic lymphocyte maturation factor). J Immunol, 147, 874–82.

    Google Scholar 

  20. Wolf SF, Temple PA, Kobayashi M, et al. 1991. Cloning of cDNA for natural killer cell stimulatory factor, a heterodimeric cytokine with multiple biological effects on T and natural killer cells. J Immunol, 146, 3074–81.

    Google Scholar 

  21. Chehimi J, Starr SE, Frank I, et al. 1992, Natural killer (NK) cell stimulatory factor increases the cytotoxic activity of NK cells from both healthy donors and human immunodeficiency virus-infected patients. J Exp Med, 175, 789–96.

    Google Scholar 

  22. Bancroft GJ, Schreiber RD and Unanue ER, 1991, Natural immunity: a T-cell independent pathway of macrophage activation, defined in the scid mouse. Immunol Rev, 124, 5–24.

    Google Scholar 

  23. Andrews JVR, Schoof DD, Bertagnolli MM, et al. 1993, Immunomodulatory effects of interleukin-12 on human tumour-infiltrating lymphocytes. J Immunol, 14, 1–10.

    Google Scholar 

  24. Chan SH, Perussia B, Gupta JW, et al. 1991, Induction of IFN-y production by NK cell stimulatory factor (NKSF): characterisation of the responder cells and synergy with other inducers. J Exp Med, 173, 869–75.

    Google Scholar 

  25. Meurs EF, Galabru J, Barber GN, Katze MG and Hovanessian AG, 1993, Tumour suppressor function of the interferon-induced double-stranded RNA-activated protein kinase. Proc Natl Acad Sci USA, 90, 232–6.

    Google Scholar 

  26. Rosen EM, Meromsky L, Setter E, Vinter DW and Goldberg I, 1990, Quantitation of cytokine-stimulated migration of endothelium and epithelium by a new assay using microcarrier beads. Exp Cell Res, 186, 22–31.

    Google Scholar 

  27. Furukawa T, Watanabe M, Kubota T, et al. 1993, Significance of in vitro attachment of human colon cancers to extracellular matrix proteins in experimental and clinical liver metastasis. J Surg Oncol, 53, 10–6.

    Google Scholar 

  28. Jiang WG, Hiscox S, Hallett MB, et al. 1995, Inhibition of hepatocyte growth factor-induced motility and in vitro invasion of human colon cancer cells by gamma-linolenic acid. Br J Cancer, 71, 744–52.

    Google Scholar 

  29. Tada H, Shiho O, Kuroshima K, Koyama M and Tsukamoto K, 1986, An improved colorimetric assay for interleukin-2. J Immunol Methods, 93, 157–65.

    Google Scholar 

  30. Albini A, Iwamoto Y, Kleinman HK, et al. 1987, A rapid in vitro assay for quantitating the invasive potential of tumour cells. Cancer Res, 47, 3239–45.

    CAS  PubMed  Google Scholar 

  31. Parish CR, Jakobsen KB and Coombe DR, 1992, A basement membrane permeability assay which correlates with the metastatic potential of tumour cells. Int J Cancer, 52, 3239–45.

    Google Scholar 

  32. Donaldson GA and Welch JP, 1974, Management of cancer of the colon. Surg Clin N Amer, 54, 713–30.

    Google Scholar 

  33. Robertson MJ, Soiffer RJ, Wolf SF, et al. 1992, Responses of human natural killer (NK) cells to NK cell stimulatory factor (NKSF): Cytolytic activity and proliferation of NK cells are differentially regulated by NKSF. J Exp Med, 175, 779–88.

    Google Scholar 

  34. Tahara H, Zeh HJ, Storkus WJ, et al. 1994, Fibroblasts genetically engineered to secrete interleukin-12 can suppress tumour growth and induce antitumour immunity to a murine melanoma in vivo. Cancer Res, 54, 182–9.

    Google Scholar 

  35. Jiang WG, Lloyds D, Puntis MCA, Nakamura T and Hallett MB, 1993, Regulation of spreading and growth of human colon cancer cells by hepatocyte growth factor. Clin Exp Metastasis, 11, 235–42.

    Google Scholar 

  36. Jiang WG, Hallett MB and Puntis MCA, 1993, Hepatocyte growth factor/scatter factor, liver regeneration and cancer metastasis. Br J Surg, 80, 1368–73.

    Google Scholar 

  37. Nakamura T, Nawa K and Ichihara A, 1984, Partial purification and characterization of hepatocyte growth factor from serum of hepatectomized rats. Biochem Biophys Res Commum, 122, 1450–59.

    Google Scholar 

  38. Stoker M, Gheradi E, Perryman M and Gray J, 1987, Scatter factor is a fibroblast-derived modulator of epithelial cell mobility. Nature, 327, 239–42.

    Article  CAS  PubMed  Google Scholar 

  39. Weidner KM, Arakaki N, Hartmann G, Birchmeier W, et al. 1991, Evidence for the identity of human scatter factor and human hepatocyte growth factor. Proc Natl' Acad Sci USA, 88, 7001–5.

    Google Scholar 

  40. Gherardi E and Stoker M, 1990, Hepatocyte and scatter factor (Letter). Nature, 346, 228.

    Google Scholar 

  41. Di Renzo MF, Olivero M and Ferro S, 1992, Overexpression of the c-MET/HGF receptor gene in human thyroid carcinomas. Oncogene, 7, 2549–53.

    Google Scholar 

  42. Ebert M, Yokoyama M, Friess H, Buchler MW and Kore M, 1994, Coexpression of the c-met protooncogene and hepatocyte growth factor in human pancreatic cancer. Cancer Res, 54, 5775–8.

    Google Scholar 

  43. Rong S, Bodescot M, Blair D, Dunn J, 1992, Tumorigenicity of the met protooncogene and the gene for hepatocyte growth factor. Mol Cell Biol, 12, 5152–8.

    Google Scholar 

  44. Behrens J, Weidner KM, Frixen UH, et al. 1991, The role of e-cadherin and scatter factor in tumour invasion and cell motility. In: Cell Motility Factors, Goldberg ID, ed. Birkharser: Basle, pp. 109–26.

    Google Scholar 

  45. Bowie GL, Caslin AW, Roland NJ, et al. 1993, Expression of cell-cell adhesion molecule E-cadherin in squamous cell carcinoma of the head and neck. Clin Otolaryngol, 18(3), 196–201.

    Google Scholar 

  46. Shimoyama Y, Hirohashi S, Hirano S, et al. 1989, Adherin cell adhesion molecules in human epithelial tissues and carcinomas. Cancer Res, 49, 2128–33.

    Google Scholar 

  47. Frixen UH, Behrens J, Sachs M et al. 1991, e-cadherinmediated cell-cell adhesion prevents invasiveness of human carcinoma cells. J Cell Biol, 113, 173–85.

    Google Scholar 

  48. Desai BB, Quin PM, Wolitzky AG, et al. 1992, IL-12 receptor. II. Distribution and regulation of receptor expression. J Immunol, 148, 3125–32.

    Google Scholar 

  49. Chua AO, Chizzonite R, Desai BB, et al. 1994, Expression cloning of a human IL-12 receptor component. J Immunol, 153, 128–36.

    Google Scholar 

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Authors and Affiliations

  1. Department of Surgery, University of Wales College of Medicine, Cardiff, UK

    Stephen Hiscox, Maurice B. Hallett, Malcom C. A. Puntis & Wen G. Jiang

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  1. Stephen Hiscox
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  2. Maurice B. Hallett
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  3. Malcom C. A. Puntis
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  4. Wen G. Jiang
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Hiscox, S., Hallett, M.B., Puntis, M.C.A. et al. Inhibition of cancer cell motility and invasion by interleukin-12. Clin Exp Metast 13, 396–404 (1995). https://doi.org/10.1007/BF00121916

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  • DOI: https://doi.org/10.1007/BF00121916

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