Nature Medicine
2, 1197 - 1203 (1996)
doi:10.1038/nm1196-1197
A polymeric form of fibronectin has antimetastatic effects against multiple tumor typesRenata Pasqualini1, Sandrine Bourdoulous1, Erkki Koivunen3, Virgil L. Woods Jr.2
& Erkki Ruoslahti1
1La Jolia Cancer Research Center, The Bumham Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, USA
2School of Medicine, University of California-San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA
3Department of Biosciences, Division of Biochemistry, Viikinkaari 5, 00014 University of Helsinki, Finland Metastasis accounts for most deaths in cancer patients. Tumor cell adhesion to the extracellular matrix through integrins is thought to be a critical step in metastasis and a potential target for therapeutic intervention. We show here that treatment of human osteosarcoma, melanoma and carcinoma cells with a polymeric form of fibronectin (sFN), before inoculation into nude mice, prevented tumor formation. Intraperitoneally administered sFN significantly reduced lung colonization from intravenously injected tumor cells (experimental metastasis) and from subcutaneous tumors in nude mice (spontaneous metastasis). Treatment with sFN blocked cell spreading and migration in vitro suggesting a possible mechanism for the antimetastatic effect.
REFERENCES
- Liotta, L.A. Tumor invasion and metastasis: Role of the extraCellular matrix [Rhoads Memorial Award Lecture]. Cancer Res. 46, 1−7 (1986). | PubMed | ISI | ChemPort |
- Hart, I.R., Goode, N.T. & Wilson, R.E. Molecular aspects of the metastatic cascade. Biochim. Biophys.Acta 989, 65−84 (1989). | Article | ChemPort |
- Fidler, I.J. & Hart, I.R. Biological diversity in metastatic neoplasms: Origins and implications. Science 217, 998−1003 (1982). | PubMed | ISI | ChemPort |
- Nicolson, G.L. Organ specificity of tumor metastasis: Role of preferential adhesion, invasion and growth of malignant Cells at specific secondary sites. Cancer Metastasis Rev. 7, 143−188 (1988). | PubMed | ISI | ChemPort |
- Zetter, B.R. Adhesion molecules in tumor metastasis. Semin. Cancer Biol. 4, 219−229 (1993). | PubMed | ISI | ChemPort |
- Springer, T.A. Traffic signals for lymphocyte recirculation and leukocyte emigration: The multistep paradigm. Cell 76, 301−314 (1994). | Article | PubMed | ISI | ChemPort |
- Ginsberg, M.H., Du, X. & Plow, E.F. Inside-out integrin signaling. Curr. Opin. Cell Biol, 4, 766−771 (1992). | Article | PubMed | ChemPort |
- Burridge, K., Petch, L.A. & Romer, L.H. Signals from focal adhesions. Curr. Biol. 2, 537−539 (1992). | ChemPort |
- Vuori, K. & Ruoslahti, E. Association of insulin receptor substrate-1 with integrins. Science 266, 1576−1578 (1994). | PubMed | ISI | ChemPort |
- Damsky, C.H. & Werb, Z. Signal transduction by integrin receptors for extraCellular matrix: Cooperative processing of extra Cellular information. Curr. Opin. Cell Biol. 4, 772−781 (1992). | Article | PubMed | ChemPort |
- Chan, B.M.C. & Hemler, M.E. Multiple functional forms of the integrin VLA-2 can be derived from a single
 2 cDNA clone: Interconversion of forms induced by an anti- l antibody. J. Cell Biol. 120, 537−543 (1993). | Article | PubMed | ISI | ChemPort |
- Arroyo, A.G., García-Pardo, A. & Sánchez-Madrid, F. A high affinity conformational state on VLA integrin heterodimers induced by an anti-1, chain monoclonal antibody. J. Biol. Chem. 268, 9863−9868 (1993). | PubMed | ISI | ChemPort |
- O Toole, T.E. et al. Affinity modulation of the IIb3, integrin (platelet GPIIb-IIIa) is an intrinsic property of the receptor. Cell Regul. 1, 883−893 (1990). | PubMed | ChemPort |
- Zhang, Z., Vuori, K., Wang, G.-G., Reed, J.C. & Ruoslahti, E. Integrin activation by R-ras. Cell 85, 61−69 (1996). | Article | PubMed | ISI | ChemPort |
- Plantefaber, L.C. & Hynes, R.O. Changes in integrin receptors on oncogenically transformed cells. Cell 56, 281−290 (1989). | Article | PubMed | ISI | ChemPort |
- Giancotti, F.G. & Mainiero, F. Integrin-mediated adhesion and signaling in tumorigenesis. Biochim. Biophys. Acta 1198, 47−64 (1994). | Article | PubMed | ISI | ChemPort |
- Nip, J., Rabbani, S.A., Shibata, H.R. & Brodt, P. Coordinated expression of the vitronectin receptor and the urokinase-type plasminogen activator in metastatic melanoma cells. J. Clin. Invest. 95, 2096−2103 (1995). | PubMed | ISI | ChemPort |
- Felding-Habermann, B., Ruggeri, Z.M. & Cheresh, D.A. Distinct biological consequences of integrin v3-mediated melanoma cell adhesion to fibrinogen and its plasmic fragments. J. Biol. Chem. 267, 5070−5077 (1992). | PubMed | ChemPort |
- Hynes, R.O., Integrins: Versatility, modulation and signaling in cell adhesion. Cell 69, 11−25 (1992). | Article | PubMed | ISI | ChemPort |
- Juliano, R.L. The role of 1, integrins in tumors. Cancer Biol. 4, 277−283 (1993). | ChemPort |
- de Boer, H.C., Preissner, K.T., Bouma, B.N. & de Groot, P.G. Internalization of vitronectin-thrombin-antithrombin complex by endothelial cells leads to deposition of the complex into the subendothelial matrix. J. Biol. Chem. 270, 30733−30740 (1995). | Article | PubMed | ChemPort |
- Werb, Z., Tremble, P.M., Behrendtsen, O., Crowley, E. & Damsky, C.H. Signal transduction through the fibronectin receptor induces collagenase and stromelysin gene expression. J. Cell Biol. 109, 877−889 (1989). | Article | PubMed | ISI | ChemPort |
- Felding-Habermann, B., Mueller, B.M., Romerdahl, C.A. & Cheresh, D.A. Involvement of integrin v, gene expression in human melanoma tumorigenicity. J. Clin. Invest. 89, 2018−2022 (1992). | PubMed | ChemPort |
- Giancotti, F.G. & Ruoslahti, E. Elevated levels of the 51, fibronectin receptor suppress the transformed phenotype of Chinese hamster ovary cells. Cell 60, 849−859 (1990). | Article | PubMed | ISI | ChemPort |
- Zutter, M.M., Santoro, S.A., Staatz, W.D. & Tsung, Y.L. Re-expression of the 21, integrin abrogates the malignant phenotype of breast carcinoma Cells. Proc. Natl. Acad. Set. USA 92, 7411−7415 (1995). | ChemPort |
- Humphries, M.J., Olden, K. & Yamada, K.M. A synthetic peptide from fibronectin inhibits experimental metastasis of murine melanoma cells. Science 233, 467−470 (1986). | PubMed | ISI | ChemPort |
- Yamada, K.M. et al. Monoclonal antibody and synthetic peptide inhibitors of human tumor cellc migration. Cancer Res. 50, 4485−4496 (1990). | PubMed | ISI | ChemPort |
- Soszka, T. et al. Inhibition of murine melanoma Cell-matrix adhesion and experimental metastasis by albolabrin an RGD-containing peptide isolated from the venom of Trimeresurus albolabris. Exp. Cell Res. 196, 6−12 (1991). | PubMed | ISI | ChemPort |
- Kumagai, H., Tajima, M., Ueno, Y., Giga-hama, Y. & Ohba, M. Effect of cyclic RGD peptide on Cell adhesion and tumor metastasis. Biochem. Biophys. Res. Commun. 177, 74−82 (1991). | PubMed | ISI | ChemPort |
- Saiki, I. et al. The inhibition of murine lung metastasis by synthetic polypeptides (poly (Arg-Gly-Asp) and poly (Tyr-Ile-Gly-Ser-Arg)] with a core sequence of cell adhesion molecules. Br. J. Cancer 59, 194−197 (1989). | PubMed | ISI | ChemPort |
- Komazawa, H. et al. The conjugate of RGDS peptide with CM-chitin augments the peptide-mediated inhibition of tumor metastasis. Carbohydr. Polym. 21, 299−307 (1993). | Article | ISI | ChemPort |
- Hardan, I. et al. Inhibition of metastatic cell colonization in murine lungs and tumor-induced morbidity by non-peptidic Arg-Gly-Asp mimetics. Int. J. Cancer 55, 1023−1028 (1993). | PubMed | ISI | ChemPort |
- Mitjans, F. et al. An anti-v-integrin antibody that blocks integrin function inhibits the development of a human melanoma in nude mice. J. Cell Sci. 108, 2825−2838 (1995). | PubMed | ISI | ChemPort |
- Brooks, P.C. et al. Integrin v3antagonists promote tumor regression by inducing apoptosis of angiogenic blood vessels. Cell 79, 1157−1164 (1994). | Article | PubMed | ISI | ChemPort |
- Chan, B.M.C., Matsuura, N., Takada, Y., Zetter, B.R. & Hemler, M.E. In vitro and in vivo consequences of VLA-expression on rhabdomyosarcoma cells. Science 251, 1600−1602 (1991). | PubMed | ISI | ChemPort |
- Qian, F., Vaux, D.L. & Weissman, I.L. Expression of the integrin 41 on melanoma Cells can inhibit the invasive stage of metastasis formation. Cell 77, 335−347 (1994). | Article | PubMed | ISI | ChemPort |
- Ruoslahti, E. Fibronectin in cell adhesion and invasion. Cancer Metastasis Rev. 3, 43−51 (1984). | PubMed | ISI | ChemPort |
- Morla, A., Zhang, Z. & Ruoslahti, E. Superfibronectin is a functionally distinct form of fibronectin. Nature 367, 193−196 (1994). | Article | PubMed | ISI | ChemPort |
- Koivunen, E., Wang, B. & Ruoslahti, E. Isolation of a highly specific ligand for the 5l integrin from a phage display library. J. Cell Biol. 124, 373−380 (1994). | Article | PubMed | ISI | ChemPort |
- Koivunen, E., Wang, B. & Ruoslahti, E. Phage libraries displaying cyclic peptides with different ring sizes: Ligand specificities of the RGD-directed integrins. BioTechnology 13, 265−270 (1995). | PubMed | ChemPort |
- Pierschbacher, M.D. & Ruoslahti, E. Influence of stereochemistry of the sequence Arg-Gly-Asp-Xxx on binding specificity in cell adhesion. J. Biol. Chem. 262, 17294−17298 (1987). | PubMed | ISI | ChemPort |
- Gotloib, L. & Shostak, A. Endocytosis and transcytosis of albumin gold through mice peritoneal mesothelium. Kidney Int. 47, 1274−1284 (1995). | PubMed | ISI | ChemPort |
- Hamilton, T.C. et al. Characterization of a human ovarian carcinoma Cell line (NIH: OVCAR-3) with androgen and estrogen receptors. Cancer Res. 43, 5379−5389 (1983). | PubMed | ISI | ChemPort |
- Blystone, S.D., Graham, I.L., Lindberg, F.P. & Brown, E.J. Integrin v3 differentially regulates adhesive and phagocytic functions of the firbronectin receptor AA51. J. Cell Biol. 127, 1129−1137 (1994). | Article | PubMed | ISI | ChemPort |
- Dohlman, H.G., Thorner, J., Caron, M.G. & Lefkowitz, R.J. Model systems for the study of seven-transmembrane-segment receptors. Annu. Rev. Biochem. 60, 653−658 (1991). | Article | PubMed | ISI | ChemPort |
- Welch, D.R. et al. Characterization of a highly invasive and spontaneously metastatic human malignant melanoma cell line. Int. J. Cancer 47, 227−237 (1991). | PubMed | ISI | ChemPort |
- Berlin, Ö. et al. Development of a novel spontaneous metastasis model of human osteosarcoma transplanted orthotopically into bone of athymic mice. Cancer Res. 53, 4890−4895 (1993). | PubMed | ISI |
- Fogh, J., Fogh, J.M. & Orfeo, T. One hundred and twenty-seven cultured human tumor Cell lines producing tumors in nude mice. J. Natl. Cancer Inst. 59, 221−226 (1977). | PubMed | ChemPort |
- Tada, H., Shiho, O., Kuroshima, K., Koyama, M. & Tsukamoto, K. An improved colorimetric assay for interleukin-2. Eur. J. Immunol. 93, 157−165 (1986). | Article | ChemPort |
- McKenown-Longo, P.J. & Mosher, D.F. Binding of plasma fibronectin to Cell layers of human skin fibroblasts. J. Cell Biol. 97, 466−472 (1983). | Article | PubMed | ChemPort |
- Pasqualini, R. & Hemler, M.E. Contrasting roles for integrin 1, and 5 cytoplasmic domains in subcellular localization, cell proliferation, and cell migration. J. Cell Biol. 125, 447−460 (1994). | Article | PubMed | ISI | ChemPort |
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