Clinical & Experimental Metastasis

, Volume 16, Issue 6, pp 541–550 | Cite as

Inhibition of tumor invasion and metastasis by calciumspirulan (Ca-SP), a novel sulfated polysaccharide derived from a blue-green alga, Spirulina platensis

  • Takaaki Mishima
  • Jun Murata
  • Minako Toyoshima
  • Hideki Fujii
  • Motowo Nakajima
  • Toshimitsu Hayashi
  • Toshimitsu Kato
  • Ikuo Saiki


We have investigated the effect of calcium spirulan (Ca-SP) isolated from a blue-green alga, Spirulinaplatensis, which is a sulfated polysaccharide chelating calcium and mainly composed of rhamnose, on inva-sionof B16-BL6 melanoma, Colon 26 M3.1 carcinoma and HT-1080 fibrosarcoma cells through reconsti-tutedbasement membrane (Matrigel). Ca-SP significantly inhibited the invasion of these tumor cells throughMatrigel/fibronectin-coated filters. Ca-SP also inhibited the haptotactic migration of tumor cells to laminin,but it had no effect on that to fibronectin. Ca-SP prevented the adhesion of B16-BL6 cells to Matrigel andlaminin substrates but did not affect the adhesion to fibronectin. The pretreatment of tumor cells withCa-SP inhibited the adhesion to laminin, while the pretreatment of laminin substrates did not. Ca-SP hadno effect on the production and activation of type IV collagenase in gelatin zymography. In contrast, Ca-SPsignificantly inhibited degradation of heparan sulfate by purified heparanase. The experimental lungmetastasis was significantly reduced by co-injection of B16-BL6 cells with Ca-SP. Seven intermittent i.v.injections of 100 mg of Ca-SP caused a marked decrease of lung tumor colonization of B16-BL6 cells in aspontaneous lung metastasis model. These results suggest that Ca-SP, a novel sulfated polysaccharide, couldreduce the lung metastasis of B16-BL6 melanoma cells, by inhibiting the tumor invasion of basementmembrane probably through the prevention of the adhesion and migration of tumor cells to laminin substrateand of the heparanase activity.©Kluwer Academic Publishers

adhesion calcium spirulan invasion laminin metastasis 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Fidler IJ, 1984, The Ernst W. Bertner Memorial Award Lecture: The evolution of biological heterogeneity in metastatic neoplasms. In: Nicolson GL and Milas L, eds. Cancer Invasion and Metastases: Biologic and Therapeutic Aspects. New York: Raven Press, pp. 5-26.Google Scholar
  2. 2.
    Gasic GJ, Gasic TB, Galanti N, et al.1973, Platelet-tumor cell interactions in mice. The role of platelets in the spread of malignant disease. Int J Cancer, 11, 704-18.Google Scholar
  3. 3.
    Hara Y, Steiner M and Baldini MG, 1980, Characterization of the platelet-aggregating activity of tumor cells. Cancer Res, 40, 1217-22.Google Scholar
  4. 4.
    Tohgo A, Tanaka N and Ogawa H, 1984, Platelet-aggregating activities of metastasizing tumor cells. II. Variety of the aggregation mechanisms. Invasion Metastasis, 4, 134-5.Google Scholar
  5. 5.
    Tsuruo T, Kawabata H, Iida H and Yamori T, 1986, Tumor-induced platelet aggregation and growth promoting factors as determinants for successful tumor metastasis. Clin Exp Metastasis, 4, 25-33.Google Scholar
  6. 6.
    Kramer RH and Nicolson GL, 1979, Interactions of tumor cells with vascular endothelial cell monolayers: a model for metastatic invasion. Proc Natl Acad Sci USA, 76, 5704-8.Google Scholar
  7. 7.
    Honn KV, Onoda JM, Diglio CA, et al.1985, Inhibition by dihydropyridine class of calcium channel blockers of tumor cell-platelet-endothelial cell interactions in vitroand metastasis in vivo. Biochem Pharmacol, 34, 235-41.Google Scholar
  8. 8.
    Yahalom J, Eldor A, Biran S, et al.1985, Platelet-tumor cell interaction with the subendothelial matrix: relationship to cancer metastasis. Radiother Oncol, 3, 211-25.Google Scholar
  9. 9.
    Menter DG, Steinert BW, Sloane BF, et al. 1987, Role of platelet membrane in enhancement of tumor cell adhesion to endothelial cell extracellular matrix. Cancer Res, 47, 6751-62.Google Scholar
  10. 10.
    Liotta LA, 1986, Tumor invasion and metastases-role of the extracellular matrix: Rhoads Memorial Award Lecture. Cancer Res, 46, 1-7.Google Scholar
  11. 11.
    Suemasu K and Ishikawa S, 1970, Inhibitive effect of heparin and dextran sulfate on experimental pulmonary metastasis. Gann, 61, 125-30.Google Scholar
  12. 12.
    Tsubura E, Yamashita T, Kobayashi M, et al.1977, Inhibitory mechanism of blood-borne pulmonary metastasis by sulfated polysaccharides. Gann Monogr Cancer Res, 20, 147-61.Google Scholar
  13. 13.
    Irimura T, Nakajima M and Nicolson GL, 1986, Chemically modified heparins as inhibitors of heparan sulfate specific endo-β-glucuronidase (heparanase) of metastatic melanoma cells. Biochemistry, 25, 5322-8.Google Scholar
  14. 14.
    Murata J, Saiki I, Nishimura S, et al.1989, Inhibitory effect of chitin heparinoids on the lung metastasis of B16-BL6 melanoma. Jpn J Cancer Res, 80, 866-72.Google Scholar
  15. 15.
    Saiki I, Murata J, Nakajima M, et al.1990, Inhibition by sulfated chitin derivatives of invasion through extracellular matrix and enzymatic degradation by metastatic melanoma cells. Cancer Res, 50, 3631-7.Google Scholar
  16. 16.
    Murata J, Saiki J, Makabe T, et al.1991, Inhibition of tumor-induced angiogenesis by sulfated chitin derivatives. Cancer Res, 51, 22-6.Google Scholar
  17. 17.
    Ciferri O, 1983, Spirulina, the edible microorganisms. Microbiol Rev, 47, 551-78.Google Scholar
  18. 18.
    Kato T, Takemoto T, Katayama H and Kuwabara Y, 1984, Effect of Spirulina(Spirulina platensis) on dietary hypercholesterolemia in rats. J Jpn Soc Nutr Food Sci, 37, 323-32.Google Scholar
  19. 19.
    Hayashi O, Katoh T and Okuwaki Y, 1994, Enhancement of antibody production in mice by dietary Spirulina platensis. J Nutr Sci Vitaminol, 40, 431-41.Google Scholar
  20. 20.
    Schwartz J, Shklar G, Reid S and Trickler D, 1988, Prevention of experimental oral cancer by extracts of Spirulina-dunaliellaalgae. Nutr Cancer, 11, 127-34.Google Scholar
  21. 21.
    Hayashi T and Hayashi K, 1996, Calcium spirulan, an inhibitor of enveloped virus replication, from a bluegreen alga Spirulina platensis. J Nat Prod, 59, 83-7.Google Scholar
  22. 22.
    Hayashi K, Hayashi T and Morita N, 1993, An extract from Spirulina platensisis a selective inhibitor of herpes simplex virus type 1 penetration into Hera cells. Phytother Res, 7, 76-80.Google Scholar
  23. 23.
    Saiki I, Murata J, Watanabe K, et al.1989, Inhibition of tumor cell invasion by ubenimex (bestatin) in vitro. Jpn J Cancer Res, 80, 873-8.Google Scholar
  24. 24.
    Saiki I, Iida J, Murata J, et al. 1989, Inhibition of the metastasis of murine malignant melanoma by synthetic polymeric peptides containing core sequences of cell-adhesive molecules. Cancer Res, 49, 3815-22.Google Scholar
  25. 25.
    Heussen C and Dowdle EB, 1980, Electrophoretic analysis of plasminogen activators in polyacrylamide gels containing sodium dodecyl sulfate and copolymerized substrates. Anal Biochem, 102, 196-202.Google Scholar
  26. 26.
    Nakajima M, DeChavigny A, Johnson CE, et al.1991, Suramin: a potent inhibitor of melanoma heparanase and invasion. J Biol Chem, 266, 9661-6.Google Scholar
  27. 27.
    Muratra J, Saiki I, Matsuno K, et al.1990, Inhibition of tumor cell arrest in lungs by antimetastatic chitin heparinoid. Jpn J Cancer Res, 81, 506-13.Google Scholar
  28. 28.
    Hans-Joachim G and Klaus K, 1989, Elucidation of similarities of sugar receptor (lectin) expression of human lung metastases from histogenetically different types of primary tumors. Anticancer Res, 9, 1599-604.Google Scholar

Copyright information

© Chapman and Hall 1998

Authors and Affiliations

  • Takaaki Mishima
    • 1
  • Jun Murata
    • 1
  • Minako Toyoshima
    • 2
  • Hideki Fujii
    • 1
  • Motowo Nakajima
    • 2
  • Toshimitsu Hayashi
    • 3
  • Toshimitsu Kato
    • 4
  • Ikuo Saiki
    • 5
  1. 1.Research Institute for Wakan-YakuChibaJapan
  2. 2.Oncology ResearchTakarazuka Research Institute, Novartis Pharma K.K.Takarazuka ChibaJapan
  3. 3.Section of Chemistry, Institute of Immunological ScienceHokkaido UniversitySapporoJapan
  4. 4.Faculty of Pharmaceutical SciencesToyama Medical and Pharmaceutical UniversityToyama
  5. 5.Biochemical DivisionDainippon Ink and Chemicals, IncChibaJapan

Personalised recommendations