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Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1986 Sep;83(17):6613–6617. doi: 10.1073/pnas.83.17.6613

Interferon gamma and granulocyte/macrophage colony-stimulating factor inhibit growth and induce antigens characteristic of myeloid differentiation in small-cell lung cancer cell lines.

M R Ruff, W L Farrar, C B Pert
PMCID: PMC386554  PMID: 3018738

Abstract

The expression of several macrophage and hemopoietic cell surface markers recently described on small-cell lung cancer (SCLC) cell lines was studied by use of flow cytometry. The antigens Leu-M3, Leu-7, and HLA-DR were examined for their modulation by human interferon gamma and granulocyte/macrophage colony-stimulating factor (GM-CSF). Both of these lymphokines generally induced enhanced expression of hemopoietic markers in several SCLC lines. A differential response to these two hormones was observed, in that qualitative and quantitative differences in marker modulation among the tested cell lines were apparent. In addition to regulating the antigenic phenotype of these cells, both interferon gamma and GM-CSF had antiproliferative effects on SCLC lines as determined by [3H]thymidine incorporation and clonal growth in agar. These results suggest that interferon gamma and GM-CSF promote a differentiation process in SCLC cell lines that has characteristics in common with myeloid differentiation. These findings support the theory that SCLC tumors are hemopoietic cells that arise from macrophages or their precursors and suggest new therapeutic modalities for the treatment of lung cancer.

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Selected References

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

  1. Abo T., Cooper M. D., Balch C. M. Characterization of HNK-1+ (Leu-7) human lymphocytes. I. Two distinct phenotypes of human NK cells with different cytotoxic capability. J Immunol. 1982 Oct;129(4):1752–1757. [PubMed] [Google Scholar]
  2. Basham T. Y., Merigan T. C. Recombinant interferon-gamma increases HLA-DR synthesis and expression. J Immunol. 1983 Apr;130(4):1492–1494. [PubMed] [Google Scholar]
  3. Becker S. Interferons as modulators of human monocyte-macrophage differentiation. I. Interferon-gamma increases HLA-DR expression and inhibits phagocytosis of zymosan. J Immunol. 1984 Mar;132(3):1249–1254. [PubMed] [Google Scholar]
  4. Bradley E. C., Ruscetti F. W. Effect of fibroblast, lymphoid, and myeloid interferons on human tumor colony formation in vitro. Cancer Res. 1981 Jan;41(1):244–249. [PubMed] [Google Scholar]
  5. Buessow S. C., Gillespie G. Y. Interferon-alpha and -gamma promote myeloid differentiation of HL-60, a human acute promyelocytic leukemia cell line. J Biol Response Mod. 1984 Dec;3(6):653–662. [PubMed] [Google Scholar]
  6. Bunn P. A., Jr, Linnoila I., Minna J. D., Carney D., Gazdar A. F. Small cell lung cancer, endocrine cells of the fetal bronchus, and other neuroendocrine cells express the Leu-7 antigenic determinant present on natural killer cells. Blood. 1985 Mar;65(3):764–768. [PubMed] [Google Scholar]
  7. Carney D. N., Gazdar A. F., Bepler G., Guccion J. G., Marangos P. J., Moody T. W., Zweig M. H., Minna J. D. Establishment and identification of small cell lung cancer cell lines having classic and variant features. Cancer Res. 1985 Jun;45(6):2913–2923. [PubMed] [Google Scholar]
  8. Chen B. D., Lin H. S. Colony-stimulating factor (CSF-1): its enhancement of plasminogen activator production and inhibition of cell growth in a mouse macrophage cell line. J Immunol. 1984 Jun;132(6):2955–2960. [PubMed] [Google Scholar]
  9. Dimitriu-Bona A., Burmester G. R., Waters S. J., Winchester R. J. Human mononuclear phagocyte differentiation antigens. I. Patterns of antigenic expression on the surface of human monocytes and macrophages defined by monoclonal antibodies. J Immunol. 1983 Jan;130(1):145–152. [PubMed] [Google Scholar]
  10. Doyle A., Martin W. J., Funa K., Gazdar A., Carney D., Martin S. E., Linnoila I., Cuttitta F., Mulshine J., Bunn P. Markedly decreased expression of class I histocompatibility antigens, protein, and mRNA in human small-cell lung cancer. J Exp Med. 1985 May 1;161(5):1135–1151. doi: 10.1084/jem.161.5.1135. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Fisher E. R., Paulson J. D. A new in vitro cell line established from human large cell variant of oat cell lung cancer. Cancer Res. 1978 Nov;38(11 Pt 1):3830–3835. [PubMed] [Google Scholar]
  12. Gazdar A. F., Bunn P. A., Jr, Minna J. D., Baylin S. B. Origin of human small cell lung cancer. Science. 1985 Aug 16;229(4714):679–680. doi: 10.1126/science.2992083. [DOI] [PubMed] [Google Scholar]
  13. Gazdar A. F., Carney D. N., Nau M. M., Minna J. D. Characterization of variant subclasses of cell lines derived from small cell lung cancer having distinctive biochemical, morphological, and growth properties. Cancer Res. 1985 Jun;45(6):2924–2930. [PubMed] [Google Scholar]
  14. Gazdar A. F., Carney D. N., Russell E. K., Sims H. L., Baylin S. B., Bunn P. A., Jr, Guccion J. G., Minna J. D. Establishment of continuous, clonable cultures of small-cell carcinoma of lung which have amine precursor uptake and decarboxylation cell properties. Cancer Res. 1980 Oct;40(10):3502–3507. [PubMed] [Google Scholar]
  15. Gresser I., Bourali C., Lévy J. P., Fontaine-Brouty-Boyé D., Thomas M. T. Increased survival in mice inoculated with tumor cells and treated with interferon preparations. Proc Natl Acad Sci U S A. 1969 May;63(1):51–57. doi: 10.1073/pnas.63.1.51. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Harris P. E., Ralph P., Litcofsky P., Moore M. A. Distinct activities of interferon-gamma, lymphokine and cytokine differentiation-inducing factors acting on the human monoblastic leukemia cell line U937. Cancer Res. 1985 Jan;45(1):9–13. [PubMed] [Google Scholar]
  17. Herzig G. P. Autologous marrow transplantation in cancer therapy. Prog Hematol. 1981;12:1–23. [PubMed] [Google Scholar]
  18. Ichikawa Y. Differentiation of a cell line of myeloid leukemia. J Cell Physiol. 1969 Dec;74(3):223–234. doi: 10.1002/jcp.1040740303. [DOI] [PubMed] [Google Scholar]
  19. Kawasaki E. S., Ladner M. B., Wang A. M., Van Arsdell J., Warren M. K., Coyne M. Y., Schweickart V. L., Lee M. T., Wilson K. J., Boosman A. Molecular cloning of a complementary DNA encoding human macrophage-specific colony-stimulating factor (CSF-1). Science. 1985 Oct 18;230(4723):291–296. doi: 10.1126/science.2996129. [DOI] [PubMed] [Google Scholar]
  20. Klimpel G. R., Fleischmann W. R., Jr, Klimpel K. D. Gamma interferon (IFN gamma) and IFN alpha/beta suppress murine myeloid colony formation (CFU-C)N: magnitude of suppression is dependent upon level of colony-stimulating factor (CSF). J Immunol. 1982 Jul;129(1):76–80. [PubMed] [Google Scholar]
  21. Lotem J., Sachs L. In vivo inhibition of the development of myeloid leukemia by injection of macrophage- and granulocyte-inducing protein. Int J Cancer. 1981 Sep 15;28(3):375–386. doi: 10.1002/ijc.2910280318. [DOI] [PubMed] [Google Scholar]
  22. Lotem J., Sachs L. In vivo inhibition of the development of myeloid leukemia by injection of macrophage- and granulocyte-inducing protein. Int J Cancer. 1981 Sep 15;28(3):375–386. doi: 10.1002/ijc.2910280318. [DOI] [PubMed] [Google Scholar]
  23. Moody T. W., Pert C. B., Gazdar A. F., Carney D. N., Minna J. D. High levels of intracellular bombesin characterize human small-cell lung carcinoma. Science. 1981 Dec 11;214(4526):1246–1248. doi: 10.1126/science.6272398. [DOI] [PubMed] [Google Scholar]
  24. Moore R. N., Larsen H. S., Horohov D. W., Rouse B. T. Endogenous regulation of macrophage proliferative expansion by colony-stimulating factor-induced interferon. Science. 1984 Jan 13;223(4632):178–181. doi: 10.1126/science.6606850. [DOI] [PubMed] [Google Scholar]
  25. Moore R. N., Oppenheim J. J., Farrar J. J., Carter C. S., Jr, Waheed A., Shadduck R. K. Production of lymphocyte-activating factor (Interleukin 1) by macrophages activated with colony-stimulating factors. J Immunol. 1980 Sep;125(3):1302–1305. [PubMed] [Google Scholar]
  26. Nagata S., Tsuchiya M., Asano S., Kaziro Y., Yamazaki T., Yamamoto O., Hirata Y., Kubota N., Oheda M., Nomura H. Molecular cloning and expression of cDNA for human granulocyte colony-stimulating factor. 1986 Jan 30-Feb 5Nature. 319(6052):415–418. doi: 10.1038/319415a0. [DOI] [PubMed] [Google Scholar]
  27. Nickoloff B. J., Basham T. Y., Merigan T. C., Morhenn V. B. Immunomodulatory and antiproliferative effect of recombinant alpha, beta, and gamma interferons on cultured human malignant squamous cell lines, SCL-1 and SW-1271. J Invest Dermatol. 1985 Jun;84(6):487–490. doi: 10.1111/1523-1747.ep12273446. [DOI] [PubMed] [Google Scholar]
  28. Patterson B. J., Robinson J. B., Pinkerton P. H. Hematopoietic cell surface markers on metastatic small cell carcinoma detected with monoclonal antibodies. Am J Clin Pathol. 1985 Aug;84(2):159–165. doi: 10.1093/ajcp/84.2.159. [DOI] [PubMed] [Google Scholar]
  29. Porvaznik M., MacVittie T. J. Detection of gap junctions between the progeny of a canine macrophage colony-forming cell in vitro. J Cell Biol. 1979 Aug;82(2):555–564. doi: 10.1083/jcb.82.2.555. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Ruff M. R., Pert C. B. Origin of human small cell lung cancer. Science. 1985 Aug 16;229(4714):680–680. doi: 10.1126/science.229.4714.680. [DOI] [PubMed] [Google Scholar]
  31. Ruff M. R., Pert C. B. Small cell carcinoma of the lung: macrophage-specific antigens suggest hemopoietic stem cell origin. Science. 1984 Sep 7;225(4666):1034–1036. doi: 10.1126/science.6089338. [DOI] [PubMed] [Google Scholar]
  32. Ruff M., Schiffmann E., Terranova V., Pert C. B. Neuropeptides are chemoattractants for human tumor cells and monocytes: a possible mechanism for metastasis. Clin Immunol Immunopathol. 1985 Dec;37(3):387–396. doi: 10.1016/0090-1229(85)90108-4. [DOI] [PubMed] [Google Scholar]
  33. Salvin S. B., Youngner J. S., Nishio J., Neta R. Tumor suppression by a lymphokine released into the circulation of mice with delayed hypersensitivity. J Natl Cancer Inst. 1975 Nov;55(5):1233–1236. doi: 10.1093/jnci/55.5.1233. [DOI] [PubMed] [Google Scholar]
  34. Souza L. M., Boone T. C., Gabrilove J., Lai P. H., Zsebo K. M., Murdock D. C., Chazin V. R., Bruszewski J., Lu H., Chen K. K. Recombinant human granulocyte colony-stimulating factor: effects on normal and leukemic myeloid cells. Science. 1986 Apr 4;232(4746):61–65. doi: 10.1126/science.2420009. [DOI] [PubMed] [Google Scholar]
  35. Steeg P. S., Moore R. N., Johnson H. M., Oppenheim J. J. Regulation of murine macrophage Ia antigen expression by a lymphokine with immune interferon activity. J Exp Med. 1982 Dec 1;156(6):1780–1793. doi: 10.1084/jem.156.6.1780. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Warren M. K., Vogel S. N. Bone marrow-derived macrophages: development and regulation of differentiation markers by colony-stimulating factor and interferons. J Immunol. 1985 Feb;134(2):982–989. [PubMed] [Google Scholar]
  37. Wong G. G., Witek J. S., Temple P. A., Wilkens K. M., Leary A. C., Luxenberg D. P., Jones S. S., Brown E. L., Kay R. M., Orr E. C. Human GM-CSF: molecular cloning of the complementary DNA and purification of the natural and recombinant proteins. Science. 1985 May 17;228(4701):810–815. doi: 10.1126/science.3923623. [DOI] [PubMed] [Google Scholar]
  38. Zauli D., Gobbi M., Crespi C., Tazzari P. L., Miserocchi F., Magnani M., Testoni N. Vimentin and keratin intermediate filaments expression by K562 leukemic cell line. Leuk Res. 1986;10(1):29–33. doi: 10.1016/0145-2126(86)90102-5. [DOI] [PubMed] [Google Scholar]

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