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The modulation of thrombospondin and other naturally occurring inhibitors of angiogenesis during tumor progression

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Summary

Fifteen different natural inhibitors of angiogenesis have now been identified that are produced by mammalian cells and are able to blockin vivo neovascularization. The majority of these are able to inhibit endothelial cell activitiesin vitro and all those tested have demonstrated significant antitumor activity. Most normal cells produce inhibitors of neovascularization that must be downregulated before the cells can develop into angiogenic, malignant tumors. In several cases the production of inhibitors ceases when tumor suppressor genes are inactivated. In the BT549 human breast carcinoma cell line, the reintroduction of a wild type p53 tumor suppressor gene resulted in the stimulation of the secretion of an inhibitor of angiogenesis, thrombospondin-1, and as a result the cells lost their angiogenic phenotype and became able to suppress angiogenesis induced by the parental tumor line. These results provide a new example of tumor suppressor gene control of a natural inhibitor of angiogenesis and add support to the concept that thrombospondin loss may play an important role in the development of some human breast cancers.

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References

  1. Dameron KM, Volpert OV, Tainsky MA, Bouck NP: Control of angiogenesis in fibroblasts by p53 regulation of thrombospondin-1. Science 265:1582–1584, 1994

    Google Scholar 

  2. Dameron KM, Volpert OV, Bouck NP: The p53 tumor suppressor gene inhibits angiogenesis by stimulating the production of thrombospondin. Cold Spring Harbor Symp Quant Biol 54:1–7, 1994

    Google Scholar 

  3. O'Reilly MS, Holmgren L, Shing Y, Chen C, Rosenthal RA, Moses M, Lane WS, Cao Y, Sage EH, Folkman J: Angiostatin: A novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma. Cell 79:315–328, 1994

    Google Scholar 

  4. Oikawa T, Hirotani K, Ogasawara H, Katayama T, Nakamura O, Iwaguchi T, Hiragun A: Inhibition of angiogenesis by vitamin D3 analogues. Eur J Pharm 178:247–250, 1990

    Google Scholar 

  5. Eisman JA, Barkla DH, Tutton PJM: Suppression ofin vivo growth of human cancer solid tumor xenografts by 1,25-dihydroxyvitamin D3. Cancer Res 47: 21–25, 1987

    Google Scholar 

  6. Yamaoka K, Marion SL, Gallegos A, Haussler MR: 1,25-dihydroxyvitamin D3 enhances the growth of tumors in thymic mice inoculated with receptor rich osteosarcoma cells. Biochem Biophys Res Commun 139:1292–1298, 1986

    Google Scholar 

  7. Sidky YA, Borden EC: Inhibition of angiogenesis by interferons: Effects on tumor- and lymphocyte-induced vascular responses. Cancer Res 47:5155–5161, 1987

    Google Scholar 

  8. Brouty-Boye D, Zetter BR: Inhibition of cell motility by interferon. Science 208:516–518, 1980

    Google Scholar 

  9. Agarwala SS, Kirkwood JM: Interferons in therapy of solid tumors. Oncology 51:129–136, 1994

    Google Scholar 

  10. Real FX, Oettgen HF, Krown SE: Kaposi's sarcoma and the acquired immunodeficiency syndrome: treatment with high and low doses of recombinant leukocyte A interferon. J Clin Oncol 4:544–551, 1986

    Google Scholar 

  11. Norioka K, Mitaka T, Mochizuki Y, Hara M, Kawagoe M, Nakamura H: Interaction of interleukin-1 and interferon-γ on fibroblast growth factor-induced angiogenesis. Jpn J Cancer Res 85:522–529, 1994

    Google Scholar 

  12. Friesel R, Komoriya A, Maciag T: Inhibition of endothelial cell proliferation by gamma-interferon. J Cell Biol 104:689–696, 1987

    Google Scholar 

  13. Tsuruoka N, Sugiyama M, Tawaragi Y, Tsujimota M, Nishihara T, Goto T, Sato N: Inhibition ofin vitro angiogenesis by lymphotoxin and interferon-γ. Biochem Biophys Res Commun 155:429–435, 1988

    Google Scholar 

  14. Maheshwari RK, Srikantan V, Bhartiya D, Kleinman HK, Grant DS: Differential effects of interferon gamma and alpha onin vitro model of angiogenesis. J Cell Phys 146:164–169, 1991

    Google Scholar 

  15. Cozzolino F, Torcia M, Aldinucci D, Ziche M, Almerigogna F, Bani D, Stern DM: Interleukin 1 is an autocrine regulator of human endothelial cell growth. Proc Natl Acad Sci USA 87:6487–6491, 1990

    Google Scholar 

  16. Nakamura S, Nakata K, Kashimoto S, Yoshida H, Yamada M: Antitumor effect of recombinant human interleukin 1 alpha against murine syngeneic tumors. Jpn J Cancer Res 77:767–773, 1986

    Google Scholar 

  17. Bani MR, Garofalo A, Scanziani E, Giavazzi R: Effect of interleukin-1-beta on metastasis formation in different tumor systems. J Natl Cancer Inst 83:119–123, 1991

    Google Scholar 

  18. Fotsis T, Zhang Y, Pepper MS, Adlercreutz H, Montesano R, Nawroth PP, Schweigerer L: The endogenous oestrogen metabolite 2-methoxyoestradiol inhibits angiogenesis and suppresses tumour growth. Nature 368:237–239, 1994

    Google Scholar 

  19. D'Amato RJ, Lin CM, Flynn E, Folkman J, Hamel E: 2-methoxyestradiol, an endogenous mammalian metabolite, inhibits tubulin polymerization by interacting at the cholchicine site. Proc Natl Acad Sci USA 91: 3964–3968, 1994

    Google Scholar 

  20. Maione TE, Gray GS, Petro J, Hunt AJ, Donner AL, Bauer SI, Carson HF, Sharpe RJ: Inhibition of angiogenesis by recombinant human platelet factor-4 and related peptides. Science 247:77–79, 1990

    Google Scholar 

  21. Sharpe RJ, Byers HR, Scott CF, Bauer SI, Maione TE: Growth inhibition of murine melanoma and human colon carcinoma by recombinant human platelet factor-4. J Natl Cancer Inst 82:848–853, 1990

    Google Scholar 

  22. Maione TE, Gray GS, Hunt AJ, Sharpe RJ: 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 51:2077–2083, 1991

    Google Scholar 

  23. Jackson D, Volpert OV, Bouck N, Linzer DIH: Stimulation and inhibition of angiogenesis by the placental proliferin and proliferin-related protein. Science 266: 1581–1584, 1994

    Google Scholar 

  24. Clapp C, Martial JA, Guzman RC, Rentier-Delrue F, Weiner RI: The 16-kilodalton N-terminal fragment of human prolactin is a potent inhibitor of angiogenesis. Endocrinol 133:1292–1299, 1993

    Google Scholar 

  25. Shapiro R, Vallee BL: Human placental ribonuclease inhibitor abolishes both angiogenic and ribonucleolytic activities of angiogenin. Proc Natl Acad Sci USA 84: 2238–2241, 1987

    Google Scholar 

  26. Polakowski IJ, Lewis MK, Muthukkaruppan VR, Erdman B, Kubai L, Auerbach R: A ribonuclease inhibitor expresses anti-angiogenic properties and leads to reduced tumor growth in mice. Am J Pathol 143: 507–516, 1993

    Google Scholar 

  27. Taylor S, Folkman J: Protamine is an inhibitor of angiogenesis. Nature 297:307–312, 1982

    Google Scholar 

  28. Neufeld G, Gospodarowicz D: Protamine sulfate inhibits mitogenic activities of the extracellular matrix and fibroblast growth factor, but potentiates that of epidermal growth factor. J Cell Phys 132:287–294, 1987

    Google Scholar 

  29. Ingber D, Folkman J: Inhibition of angiogenesis through modulation of collagen metabolism. Lab Invest 59:44–51, 1988

    Google Scholar 

  30. Oikawa T, Hirotani K, Nakamura O, Shudo K, Hiragun A, Iwaguchi T: A highly potent antiangiogenic activity of retinoids. Cancer Lett 48:157–162, 1989

    Google Scholar 

  31. Lingen MW, Bouck NP, Polverini PJ: Retinoic acid is an effective antiangiogenic agent in IL-8 producing oral squamous cell carcinomas [abstract]. Proc Amer Assoc Cancer Res 35:A389, 1994

    Google Scholar 

  32. Bollag W, Holdener EE: Retinoids in cancer prevention and therapy. Ann Oncol 3:513–526, 1992

    Google Scholar 

  33. Rastinejad F, Polverini PJ, Bouck NP: Regulation of the activity of a new inhibitor of angiogenesis by a cancer suppressor gene. Cell 56:345–355, 1989

    Google Scholar 

  34. Good DJ, Polverini PJ, Rastinejad F, LeBeau MM, Lemons RS, Frazier WA, Bouck NP: A tumor suppressor-dependent inhibitor of angiogenesis is immunologically and functionally indistinguishable from a fragment of thrombospondin. Proc Natl Acad Sci USA 87:6624–6628, 1990

    Google Scholar 

  35. Tolsma SS, Volpert OV, Good DJ, Frazier WA, Polverini PJ, Bouck N: Peptides derived from two separate domains of the matrix protein thrombospondin-1 have anti-angiogenic activity. J Cell Biol 122:497–511, 1993

    Google Scholar 

  36. Bagavandoss P, Wilks JW: Specific inhibition of endothelial cell proliferation by thrombospondin. Biochem Biophys Res Commun 170:867–872, 1990

    Google Scholar 

  37. Taraboletti G, Roberts D, Liotta LA, Giavazzi R: Platelet thrombospondin modulates endothelial cell adhesion, motility and growth: a potential angiogenesis regulatory factor. J Cell Biol 111:765–772, 1990

    Google Scholar 

  38. Iruela-Arispe ML, Bornstein P, Sage H: Thrombospondin exerts an antiangiogenic effect on cord formation by endothelial cells in vitro. Proc Natl Acad Sci USA 88:5026–5030, 1991

    Google Scholar 

  39. Tolsma SS, Volpert OV, Lai CK, Bouck N: Antiangiogenic activity of thrombospondin-1 and its peptides [abstract]. Mol Biol Cell 5(Suppl):176a, 1994

    Google Scholar 

  40. DiPietro LA, Nebgen DR, Polverini PJ: Downregulation of endothelial cell thrombospondin 1 enhancesin vitro angiogenesis. J Vasc Res 31:178–185, 1994

    Google Scholar 

  41. Tolsma SS, Volpert O, Bouck N: Tsp-1 and its peptides block angiogenesis by making endothelial cells refractory to stimuli and by enhancing differentiation [abstract]. J Cell Biochem Suppl 18A:335, 1994

    Google Scholar 

  42. Moses MA, Sudhalter J, Langer R: Identification of an inhibitor of neovascularization from cartilage. Science 248:1408–1410, 1990

    Google Scholar 

  43. Murphy AN, Unsworth EJ, Stetler-Stevenson WG: Tissue inhibitor of metalloproteinases-2 inhibits bFGF-induced human microvascular endothelial cell proliferation. J Cell Phys 157:351–358, 1993

    Google Scholar 

  44. Johnson MD, Kim HC, Chesler L, Tsao-Wu G, Bouck N, Polverini PJ: Inhibition of angiogenesis by tissue inhibitor of metalloproteinase. J Cell Phys 160:194–202, 1994

    Google Scholar 

  45. Khokha R: Suppression of the tumorigenic and metastatic abilities of murine B16-F10 melanoma cellsin vivo by the overexpression of the tissue inhibitor of metalloproteinases-1. J Natl Cancer Inst 86:299–304, 1994

    Google Scholar 

  46. Schneider J, Kinne D, Fracchia A, Pierce V, Anderson KE, Bradlow HL, Fishman J: Abnormal oxidative metabolism of estradiol in women with breast cancer. Proc Natl Acad Sci USA 79:3047–3051, 1982

    Google Scholar 

  47. Michnovicz JJ, Hershcopf RJ, Naganuma H, Bradlow HL, Fishman J: Increased 2-hydroxylation of estradiol as a possible mechanism for the anti-estrogenic effect of cigarette smoking. N Engl J Med 315:1305–1309, 1986

    Google Scholar 

  48. Van Meir EG, Polverini PJ, Chazin VR, Su Huang HJ, de Tribolet N, Cavenee WK: Release of an inhibitor of angiogenesis upon induction of wild type p53 expression in glioblastoma cells. Nature Genetics 8:171–176, 1994

    Google Scholar 

  49. Hsu SC, Volpert OV, Steck PA, Mikkelsen T, Polverini PJ, Cavenee WK, Bouck NP: Chromosome 10 regulates the angiogenic phenotype in glioblastoma cells by modulating thrombospondin [abstract]. Proc Amer Assoc Cancer Res 35:67, 1994

    Google Scholar 

  50. Clezardin P, Frappart L, Clerget M, Pechoux C, Delmas PD: Expression of thrombospondin (TSP1) and its receptors (CD36 and CD51) in normal, hyperplastic, and neoplastic human breast. Cancer Res 53: 1421–1430, 1993

    Google Scholar 

  51. Wong SY, Purdie AT, Han P: Thrombospondin and other possible related matrix proteins in malignant and benign breast disease. Am J Pathol 140:1473–1482, 1992

    Google Scholar 

  52. Tuszynski GP, Nicosia RF: Localization of thrombospondin and its cysteine-serine-valine-threonine-cysteine-glycine-specific receptor in human breast carcinoma. Lab Invest 70:228–233,1994

    Google Scholar 

  53. Zajchowski DA, Band V, Trask DK, Kling D, Connolly JL, Sager R: Suppression of tumor-forming ability and related traits in MCF-7 human breast cancer cells by fusion with immortal mammary epithelial cells. Proc Natl Acad Sci USA 87:2314–2318, 1990

    Google Scholar 

  54. Weinstat-Saslow DL, Zabrenetzky VS, VanHoutte K, Frazier WA, Roberts DD, Steeg PS: Transfection of thrombospondin 1 complementary DNA into a human breast carcinoma cell line reduces primary tumor growth, metastatic potential and angiogenesis. Cancer Res 54:6504–6511, 1994

    Google Scholar 

  55. Cox LA, Chen G, Lee EYHP: Tumor suppressor genes and their roles in breast cancer. Breast Cancer Res Treat 32:19–38,1994

    Google Scholar 

  56. Wang NP, To H, Lee W-H, Lee EYHP: Tumor suppressor activity of RB and p53 genes in human breast carcinoma cells. Oncogene 8:279–288,1993

    Google Scholar 

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Authors and Affiliations

  1. Department of Microbiology-Immunology and R.H. Lurie Cancer Center, Northwestern University, 303 East Chicago Avenue, 60611, Chicago, IL, USA

    Olga V. Volpert, Veronica Stellmach & Noel Bouck

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  1. Olga V. Volpert
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  2. Veronica Stellmach
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Volpert, O.V., Stellmach, V. & Bouck, N. The modulation of thrombospondin and other naturally occurring inhibitors of angiogenesis during tumor progression. Breast Cancer Res Tr 36, 119–126 (1995). https://doi.org/10.1007/BF00666034

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