Nature 316, 823 - 826 (29 August 1985); doi:10.1038/316823a0

Bombesin-like peptides can function as autocrine growth factors in human small-cell lung cancer

Frank Cuttitta, Desmond N. Carney, James Mulshine, Terry W. Moody^*, Joseph Fedorko, Adam Fischler & John D. Minna

National Cancer Institute-Navy Medical Oncology Branch, Division of Cancer Treatment, National Cancer Institute and Naval Hospital, Bethesda, Maryland 20814, USA
^*Department of Biochemistry, George Washington University School of Medicine and Health Science, Washington, DC 20037, USA

The autocrine hypothesis proposes that a cell produces and secretes a hormone-like substance that can interact with specific membrane receptors on its surface to induce effects such as proliferation¹. Thus, a cancer cell could act to stimulate its own growth. Bombesin and bombesin-like peptides (BLPs) such as gastrin-releasing pep-tide (GRP) cause various physiological responses in mammals², including stimulation of proliferation of 3T3 mouse fibroblasts³ and normal human bronchial epithelial cells in vitro ⁴ and induction of gastrin cell hyperplasia and increased pancreatic DNA content in vivo in rats^5,6. Human small-cell lung cancer (SCLC) cell lines produce and secrete BLPs⁷⁻¹² and can express a single class of high-affinity receptors for BLPs¹³. Exogenously added BLPs can also stimulate the clonal growth and DNA synthesis of SCLC in vitro ^14,15. These findings suggest that BLPs function as autocrine growth factors for this tumour. One way to test this hypothesis is to interrupt the function of the endogenously produced BLPs. Here, we demonstrate that a monoclonal antibody to bombesin binds to the C-terminal region of BLPs, blocks the binding of the hormone to cellular receptors and inhibits the clonal growth of SCLC in vitro and the growth of SCLC xenografts in vivo. These results demonstrate that BLPs can function as autocrine growth factors for human SCLC.

References

1.	Sporn, M. B. & Todaro, G. J. New Engl. J. Med. 303, 878−880 (1980).
2.	Erspamer, V. in Gastrointestinal Hormones (ed. Glass, G. B. J.) 343−361 (Raven, New York, 1980).
3.	Rosengurt, E. & Sinnett-Smith, J. Proc. natn. Acad. Sci. U.S.A. 80, 2936−2940 (1983).
4.	Willey, J. C., Lechner, J. R. & Harris, C. C. Expl. Cell Res. 153, 245 (1984).
5.	Lehy, T., Accary, J. P., Labeille, D. & Dubrasquet, M. Gastroenterology 84, 914−919 (1983).
6.	Lezoche, E. et al. in Gut Hormones (eds Bloom, S. R. & Polak, J. M.) 419−424 (Churchill Livingstone, London, 1981).
7.	Moody, T. W., Pert, C. B., Gazdar, A. F., Carney, D. N. & Minna, J. D. Science 214, 1246−1248 (1981).
8.	Wood, S. M. et al. J. din. Endocr. Metab. 53, 1310−1312 (1981).
9.	Erisman, M. D., Linnoila, R. I., Hernandez, O., DiAugustine, R. P. & Lazarus, L. H. Proc. natn. Acad. Sci. U.S.A. 79, 2379−2383 (1982).
10.	Yamaguchi, K. et al. Cancer Res. 43, 2332−3939 (1983).
11.	Moody, T. W., Russell, E. K., O'Donohue, T. L., Linden, C. D. & Gazdar, A. F. Life Sci. 32, 487−493 (1983).
12.	Sorenson, G. D. et al. Reg. Peptides 4, 59−66 (1982).
13.	Moody, T. W., Carney, D. N., Cuttitta, F., Quattrochi, K., Gazdar, A. F. & Minna, J. D. Life Sci. 37, 105−113 (1985).
14.	Carney, D. N. et al. Clin. Res. 31, 404A (1983).
15.	Weber, S. et al. J. Clin. Invest. 75, 306−309 (1985).
16.	Moody, T. W., Pert, C. B., Rivier, J. & Brown, M. R. natn. Acad. Sci. U.S.A. 75, 5372−5376 (1978).
17.	Westendorf, J. M. & Schonbrunn, A. J. biol. Chem. 258, 7527−7535 (1983).
18.	McDonald, T. J. et al. Biochem. biophys. Res. Commun. 90, 227−233 (1979).
19.	Spindel, E. R. et al. Proc. natn. Acad. Sci. U.S.A. 81, 5699−5703 (1984).
20.	River, J. E. & Brown, M. R. Biochemistry 17, 1766−1771 (1978).
21.	Carney, D. N. et al. Cancer Res. 45, 2913−2923 (1985).
22.	Little, C. D., Nau, M. M., Carney, D. N., Gazdar, A. F. & Minna, J. D. Nature 306, 194−196 (1983).
23.	Gazdar, A. F. et al. Cancer Res. 40, 3502−3507 (1980).
24.	Moody, T. W. & Pert, C. B. Biochem. biophys. Res. Commun. 90, 7−14 (1979).
25.	Kearney, J. F., Radbruch, A., Liesegang, B. & Rajewsky, K. J. Immun. 123, 1548−1550 (1979).
26.	Minna, J. D. et al. In Vitro 17, 1058−1070 (1981).
27.	Heide, K. & Schwick, H. G. in Handbook of Experimental Immunology (ed. Weir, D. M.) 7.1−7.11 (Blackwell Scientific, Oxford, 1978).
28.	Handley, H. H., Glassy, M. C., Cleveland, P. H. & Royston, I. J. immun. Meth. 54, 291−296 (1982).
29.	Carney, D. N., Bunn, P. A., Gazdar, A. F., Pagan, J. A. & Minna, J. D. Proc. natn. Acad. Sci. U.S.A. 78, 3185−3189 (1981).
30.	Moody, T. W., Bertness, V. & Carney, D. N. Peptides 4, 683−686 (1983).