Skip to main content
PMC home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1996 Sep 1;184(3):981–992. doi: 10.1084/jem.184.3.981

Interferon-gamma-inducible protein 10 (IP-10) is an angiostatic factor that inhibits human non-small cell lung cancer (NSCLC) tumorigenesis and spontaneous metastases

PMCID: PMC2192788  PMID: 9064358

Abstract

The success of solid tumor growth and metastasis is dependent upon angiogenesis. Neovascularization within the tumor is regulated, in part, by a dual and opposing system of angiogenic and angiostatic factors. We now report that IP-10, a recently described angiostatic factor, as a potent angiostatic factor that regulates non-small cell lung cancer (NSCLC)-derived angiogenesis, tumor growth, and spontaneous metastasis. We initially found significantly elevated levels of IP-10 in freshly isolated human NSCLC samples of squamous cell carcinoma (SCCA). In contrast, levels of IP-10 were equivalent in either normal lung tissue or adenocarcinoma specimens. The neoplastic cells in specimens of SCCA were the predominant cells that appeared to express IP-10 by immunolocalization. Neutralization of IP-10 in SCCA tumor specimens resulted in enhanced tumor-derived angiogenic activity. Using a model of human NSCLC tumorigenesis in SCID mice, we found that NSCLC tumor growth was inversely correlated with levels of plasma or tumor- associated IP-10. IP-10 in vitro functioned as neither an autocrine growth factor nor as an inhibitor of proliferation of the NSCLC cell lines. Reconstitution of intratumor IP-10 for a period of 8 wk resulted in a significant inhibition of tumor growth, tumor-associated angiogenic activity and neovascularization, and spontaneous lung metastases, whereas, neutralization of IP-10 for 10 wk augmented tumor growth. These findings support the notion that tumor-derived IP-10 is an important endogenous angiostatic factor in NSCLC.

Full Text

The Full Text of this article is available as a PDF (2.7 MB).

Selected References

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

  1. Angiolillo A. L., Sgadari C., Taub D. D., Liao F., Farber J. M., Maheshwari S., Kleinman H. K., Reaman G. H., Tosato G. Human interferon-inducible protein 10 is a potent inhibitor of angiogenesis in vivo. J Exp Med. 1995 Jul 1;182(1):155–162. doi: 10.1084/jem.182.1.155. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bacon K. B., Westwick J., Camp R. D. Potent and specific inhibition of IL-8-, IL-1 alpha- and IL-1 beta-induced in vitro human lymphocyte migration by calcium channel antagonists. Biochem Biophys Res Commun. 1989 Nov 30;165(1):349–354. doi: 10.1016/0006-291x(89)91076-0. [DOI] [PubMed] [Google Scholar]
  3. Beckett W. S. Epidemiology and etiology of lung cancer. Clin Chest Med. 1993 Mar;14(1):1–15. [PubMed] [Google Scholar]
  4. Boorsma D. M., de Haan P., Willemze R., Stoof T. J. Human growth factor (huGRO), interleukin-8 (IL-8) and interferon-gamma-inducible protein (gamma-IP-10) gene expression in cultured normal human keratinocytes. Arch Dermatol Res. 1994;286(8):471–475. doi: 10.1007/BF00371574. [DOI] [PubMed] [Google Scholar]
  5. Brem H., Gresser I., Grosfeld J., Folkman J. The combination of antiangiogenic agents to inhibit primary tumor growth and metastasis. J Pediatr Surg. 1993 Oct;28(10):1253–1257. doi: 10.1016/s0022-3468(05)80308-2. [DOI] [PubMed] [Google Scholar]
  6. Caamano J., Ruggeri B., Momiki S., Sickler A., Zhang S. Y., Klein-Szanto A. J. Detection of p53 in primary lung tumors and nonsmall cell lung carcinoma cell lines. Am J Pathol. 1991 Oct;139(4):839–845. [PMC free article] [PubMed] [Google Scholar]
  7. Clark R. A. Basics of cutaneous wound repair. J Dermatol Surg Oncol. 1993 Aug;19(8):693–706. doi: 10.1111/j.1524-4725.1993.tb00413.x. [DOI] [PubMed] [Google Scholar]
  8. Dameron K. M., Volpert O. V., Tainsky M. A., Bouck N. Control of angiogenesis in fibroblasts by p53 regulation of thrombospondin-1. Science. 1994 Sep 9;265(5178):1582–1584. doi: 10.1126/science.7521539. [DOI] [PubMed] [Google Scholar]
  9. Folkman J., Cotran R. Relation of vascular proliferation to tumor growth. Int Rev Exp Pathol. 1976;16:207–248. [PubMed] [Google Scholar]
  10. Folkman J. Seminars in Medicine of the Beth Israel Hospital, Boston. Clinical applications of research on angiogenesis. N Engl J Med. 1995 Dec 28;333(26):1757–1763. doi: 10.1056/NEJM199512283332608. [DOI] [PubMed] [Google Scholar]
  11. Gattass C. R., King L. B., Luster A. D., Ashwell J. D. Constitutive expression of interferon gamma-inducible protein 10 in lymphoid organs and inducible expression in T cells and thymocytes. J Exp Med. 1994 Apr 1;179(4):1373–1378. doi: 10.1084/jem.179.4.1373. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Gimbrone M. A., Jr, Leapman S. B., Cotran R. S., Folkman J. Tumor dormancy in vivo by prevention of neovascularization. J Exp Med. 1972 Aug 1;136(2):261–276. doi: 10.1084/jem.136.2.261. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Good D. J., Polverini P. J., Rastinejad F., Le Beau M. M., Lemons R. S., Frazier W. A., Bouck N. P. A tumor suppressor-dependent inhibitor of angiogenesis is immunologically and functionally indistinguishable from a fragment of thrombospondin. Proc Natl Acad Sci U S A. 1990 Sep;87(17):6624–6628. doi: 10.1073/pnas.87.17.6624. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Gusella G. L., Musso T., Bosco M. C., Espinoza-Delgado I., Matsushima K., Varesio L. IL-2 up-regulates but IFN-gamma suppresses IL-8 expression in human monocytes. J Immunol. 1993 Sep 1;151(5):2725–2732. [PubMed] [Google Scholar]
  15. Gómez-Chiarri M., Hamilton T. A., Egido J., Emancipator S. N. Expression of IP-10, a lipopolysaccharide- and interferon-gamma-inducible protein, in murine mesangial cells in culture. Am J Pathol. 1993 Feb;142(2):433–439. [PMC free article] [PubMed] [Google Scholar]
  16. Hu D. E., Hori Y., Fan T. P. Interleukin-8 stimulates angiogenesis in rats. Inflammation. 1993 Apr;17(2):135–143. doi: 10.1007/BF00916100. [DOI] [PubMed] [Google Scholar]
  17. Kaplan G., Luster A. D., Hancock G., Cohn Z. A. The expression of a gamma interferon-induced protein (IP-10) in delayed immune responses in human skin. J Exp Med. 1987 Oct 1;166(4):1098–1108. doi: 10.1084/jem.166.4.1098. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Kim K. J., Li B., Winer J., Armanini M., Gillett N., Phillips H. S., Ferrara N. Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature. 1993 Apr 29;362(6423):841–844. doi: 10.1038/362841a0. [DOI] [PubMed] [Google Scholar]
  19. Koch A. E., Burrows J. C., Polverini P. J., Cho M., Leibovich S. J. Thiol-containing compounds inhibit the production of monocyte/macrophage-derived angiogenic activity. Agents Actions. 1991 Nov;34(3-4):350–357. doi: 10.1007/BF01988728. [DOI] [PubMed] [Google Scholar]
  20. 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]
  21. Koch A. E., Polverini P. J., Leibovich S. J. Stimulation of neovascularization by human rheumatoid synovial tissue macrophages. Arthritis Rheum. 1986 Apr;29(4):471–479. doi: 10.1002/art.1780290403. [DOI] [PubMed] [Google Scholar]
  22. Luster A. D., Greenberg S. M., Leder P. The IP-10 chemokine binds to a specific cell surface heparan sulfate site shared with platelet factor 4 and inhibits endothelial cell proliferation. J Exp Med. 1995 Jul 1;182(1):219–231. doi: 10.1084/jem.182.1.219. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Luster A. D., Leder P. IP-10, a -C-X-C- chemokine, elicits a potent thymus-dependent antitumor response in vivo. J Exp Med. 1993 Sep 1;178(3):1057–1065. doi: 10.1084/jem.178.3.1057. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Luster A. D., Unkeless J. C., Ravetch J. V. Gamma-interferon transcriptionally regulates an early-response gene containing homology to platelet proteins. Nature. 1985 Jun 20;315(6021):672–676. doi: 10.1038/315672a0. [DOI] [PubMed] [Google Scholar]
  25. Maione T. E., Gray G. S., Hunt A. J., Sharpe R. J. Inhibition of tumor growth in mice by an analogue of platelet factor 4 that lacks affinity for heparin and retains potent angiostatic activity. Cancer Res. 1991 Apr 15;51(8):2077–2083. [PubMed] [Google Scholar]
  26. Maione T. E., Gray G. S., Hunt A. J., Sharpe R. J. Inhibition of tumor growth in mice by an analogue of platelet factor 4 that lacks affinity for heparin and retains potent angiostatic activity. Cancer Res. 1991 Apr 15;51(8):2077–2083. [PubMed] [Google Scholar]
  27. Maione T. E., Gray G. S., Petro J., Hunt A. J., Donner A. L., Bauer S. I., Carson H. F., Sharpe R. J. Inhibition of angiogenesis by recombinant human platelet factor-4 and related peptides. Science. 1990 Jan 5;247(4938):77–79. doi: 10.1126/science.1688470. [DOI] [PubMed] [Google Scholar]
  28. Majewski S., Szmurlo A., Marczak M., Jablonska S., Bollag W. Synergistic effect of retinoids and interferon alpha on tumor-induced angiogenesis: anti-angiogenic effect on HPV-harboring tumor-cell lines. Int J Cancer. 1994 Apr 1;57(1):81–85. doi: 10.1002/ijc.2910570115. [DOI] [PubMed] [Google Scholar]
  29. Matsuzaki K., Yoshitake Y., Matuo Y., Sasaki H., Nishikawa K. Monoclonal antibodies against heparin-binding growth factor II/basic fibroblast growth factor that block its biological activity: invalidity of the antibodies for tumor angiogenesis. Proc Natl Acad Sci U S A. 1989 Dec;86(24):9911–9915. doi: 10.1073/pnas.86.24.9911. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Mette S. A., Pilewski J., Buck C. A., Albelda S. M. Distribution of integrin cell adhesion receptors on normal bronchial epithelial cells and lung cancer cells in vitro and in vivo. Am J Respir Cell Mol Biol. 1993 May;8(5):562–572. doi: 10.1165/ajrcmb/8.5.562. [DOI] [PubMed] [Google Scholar]
  31. Miller J. W., Stinson W. G., Folkman J. Regression of experimental iris neovascularization with systemic alpha-interferon. Ophthalmology. 1993 Jan;100(1):9–14. doi: 10.1016/s0161-6420(93)31712-4. [DOI] [PubMed] [Google Scholar]
  32. Miller M. D., Krangel M. S. Biology and biochemistry of the chemokines: a family of chemotactic and inflammatory cytokines. Crit Rev Immunol. 1992;12(1-2):17–46. [PubMed] [Google Scholar]
  33. Momiki S., Baba M., Caamano J., Iizasa T., Nakajima M., Yamaguchi Y., Klein-Szanto A. In vivo and in vitro invasiveness of human lung carcinoma cell lines. Invasion Metastasis. 1991;11(2):66–75. [PubMed] [Google Scholar]
  34. O'Reilly M. S., Holmgren L., Shing Y., Chen C., Rosenthal R. A., Moses M., Lane W. S., Cao Y., Sage E. H., Folkman J. Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma. Cell. 1994 Oct 21;79(2):315–328. doi: 10.1016/0092-8674(94)90200-3. [DOI] [PubMed] [Google Scholar]
  35. Oppenheim J. J., Zachariae C. O., Mukaida N., Matsushima K. Properties of the novel proinflammatory supergene "intercrine" cytokine family. Annu Rev Immunol. 1991;9:617–648. doi: 10.1146/annurev.iy.09.040191.003153. [DOI] [PubMed] [Google Scholar]
  36. Pober J. S., Gimbrone M. A., Jr, Cotran R. S., Reiss C. S., Burakoff S. J., Fiers W., Ault K. A. Ia expression by vascular endothelium is inducible by activated T cells and by human gamma interferon. J Exp Med. 1983 Apr 1;157(4):1339–1353. doi: 10.1084/jem.157.4.1339. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Polverini P. J., Cotran P. S., Gimbrone M. A., Jr, Unanue E. R. Activated macrophages induce vascular proliferation. Nature. 1977 Oct 27;269(5631):804–806. doi: 10.1038/269804a0. [DOI] [PubMed] [Google Scholar]
  38. Rastinejad F., Polverini P. J., Bouck N. P. Regulation of the activity of a new inhibitor of angiogenesis by a cancer suppressor gene. Cell. 1989 Feb 10;56(3):345–355. doi: 10.1016/0092-8674(89)90238-9. [DOI] [PubMed] [Google Scholar]
  39. Rolfe M. W., Kunkel S. L., Standiford T. J., Chensue S. W., Allen R. M., Evanoff H. L., Phan S. H., Strieter R. M. Pulmonary fibroblast expression of interleukin-8: a model for alveolar macrophage-derived cytokine networking. Am J Respir Cell Mol Biol. 1991 Nov;5(5):493–501. doi: 10.1165/ajrcmb/5.5.493. [DOI] [PubMed] [Google Scholar]
  40. Sidky Y. A., Borden E. C. Inhibition of angiogenesis by interferons: effects on tumor- and lymphocyte-induced vascular responses. Cancer Res. 1987 Oct 1;47(19):5155–5161. [PubMed] [Google Scholar]
  41. Smith D. R., Kunkel S. L., Standiford T. J., Chensue S. W., Rolfe M. W., Orringer M. B., Whyte R. I., Burdick M. D., Danforth J. M., Gilbert A. R. The production of interleukin-1 receptor antagonist by human bronchogenic carcinoma. Am J Pathol. 1993 Sep;143(3):794–803. [PMC free article] [PubMed] [Google Scholar]
  42. 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]
  43. Standiford T. J., Kunkel S. L., Basha M. A., Chensue S. W., Lynch J. P., 3rd, Toews G. B., Westwick J., Strieter R. M. Interleukin-8 gene expression by a pulmonary epithelial cell line. A model for cytokine networks in the lung. J Clin Invest. 1990 Dec;86(6):1945–1953. doi: 10.1172/JCI114928. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Stout A. J., Gresser I., Thompson W. D. Inhibition of wound healing in mice by local interferon alpha/beta injection. Int J Exp Pathol. 1993 Feb;74(1):79–85. [PMC free article] [PubMed] [Google Scholar]
  45. Strieter R. M., Kunkel S. L., Arenberg D. A., Burdick M. D., Polverini P. J. Interferon gamma-inducible protein 10 (IP-10), a member of the C-X-C chemokine family, is an inhibitor of angiogenesis. Biochem Biophys Res Commun. 1995 May 5;210(1):51–57. doi: 10.1006/bbrc.1995.1626. [DOI] [PubMed] [Google Scholar]
  46. 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]
  47. Strieter R. M., Polverini P. J., Kunkel S. L., Arenberg D. A., Burdick M. D., Kasper J., Dzuiba J., Van Damme J., Walz A., Marriott D. The functional role of the ELR motif in CXC chemokine-mediated angiogenesis. J Biol Chem. 1995 Nov 10;270(45):27348–27357. doi: 10.1074/jbc.270.45.27348. [DOI] [PubMed] [Google Scholar]
  48. Symington F. W. Lymphotoxin, tumor necrosis factor, and gamma interferon are cytostatic for normal human keratinocytes. J Invest Dermatol. 1989 Jun;92(6):798–805. doi: 10.1111/1523-1747.ep12696816. [DOI] [PubMed] [Google Scholar]
  49. Tsuruoka N., Sugiyama M., Tawaragi Y., Tsujimoto M., Nishihara T., Goto T., Sato N. Inhibition of in vitro angiogenesis by lymphotoxin and interferon-gamma. Biochem Biophys Res Commun. 1988 Aug 30;155(1):429–435. doi: 10.1016/s0006-291x(88)81104-5. [DOI] [PubMed] [Google Scholar]
  50. Ueki N., Nakazato M., Ohkawa T., Ikeda T., Amuro Y., Hada T., Higashino K. Excessive production of transforming growth-factor beta 1 can play an important role in the development of tumorigenesis by its action for angiogenesis: validity of neutralizing antibodies to block tumor growth. Biochim Biophys Acta. 1992 Oct 27;1137(2):189–196. doi: 10.1016/0167-4889(92)90201-l. [DOI] [PubMed] [Google Scholar]
  51. Van Meir E. G., Polverini P. J., Chazin V. R., Su Huang H. J., de Tribolet N., Cavenee W. K. Release of an inhibitor of angiogenesis upon induction of wild type p53 expression in glioblastoma cells. Nat Genet. 1994 Oct;8(2):171–176. doi: 10.1038/ng1094-171. [DOI] [PubMed] [Google Scholar]
  52. Zucker S., Lysik R. M., Malik M., Bauer B. A., Caamano J., Klein-Szanto A. J. Secretion of gelatinases and tissue inhibitors of metalloproteinases by human lung cancer cell lines and revertant cell lines: not an invariant correlation with metastasis. Int J Cancer. 1992 Sep 30;52(3):366–371. doi: 10.1002/ijc.2910520307. [DOI] [PubMed] [Google Scholar]

Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press

RESOURCES