Basic Fibroblast Growth Factor Expression in Endothelial Cells: An Autocrine Role in Angiogenesis?

  • Anna Gualandris
  • Marco Rusnati
  • Patrizia Dell’Era
  • Daniela Coltrini
  • Elena Tanghetti
  • Emanuele Nelli
  • Marco Presta
Part of the NATO ASI Series book series (NSSA, volume 285)


bFGF belongs to the family of the heparin-binding growth factors (Basilico and Moscatelli, 1992). The single copy human bFGF gene encodes multiple bFGF isoforms with molecular weights ranging from 24 kD to 18 kD. High molecular weight isoforms (HMW-bFGFs) are colinear NH2-terminal extensions of the better characterized 18 kD protein (Florkiewicz and Sommer, 1989). Both low and high molecular weight bFGFs exert angiogenic activity in vivo and induce cell proliferation, protease production, and Chemotaxis in cultured endothelial cells (Gualandris et al., 1994). Also, bFGF has been shown to stimulate endothelial cells to form capillary-like structures in collagen gels (Montesano et al., 1986) and to invade the amniotic membrane in vitro (Mignatti et al, 1989). The phenotype induced in vitro by bFGF in endothelial cells includes also modulation of integrin expression (Klein et al., 1993), gap-junctional intercellular communication (Pepper and Meda, 1992) and urokinase receptor upregulation (Mignatti et al., 1991). Experiments performed with neutralizing anti-bFGF antibodies have implicated endogenous bFGF in wound repair (Broadley et al., 1989), vascularization of the chorioallantoic membrane during chick embryo development (Ribatti et al., 1995), and tumor growth (Baird et al., 1986; Gross et al., 1993).


Basic Fibroblast Growth Factor Angiogenic Response Human Amniotic Membrane bFGF Expression Autocrine Role 
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  1. Baird, A., P. Mormède, and P. Bohlen. 1986. Immunoreactive fibroblast growth factor (FGF) in a transplantable chondrosarcoma: inhibition of tumor growth by antibodies to FGF. J. Cell. Biochem. 30:79–85.PubMedCrossRefGoogle Scholar
  2. Basilico, C., and D. Moscatelli. 1992. The FGF family of growth factors and oncogenes. Adv. Cancer Res. 59:115–165.PubMedCrossRefGoogle Scholar
  3. Broadly K.N., A.M. Aquino, S.C. Woodward, A. Buckley-Sturrock, Y. Sato, D.B. Rifkin, and J.M. Davidson. 1989. Monospecific antibodies implicate basic fibroblast growth factor in normal wound repair. Lab. Invest. 61:571–575.Google Scholar
  4. Cozzolino, F., M. Torcia, M. Lucibello, L. Morbidelli, M. Ziehe, J. Platt, S. Fabiani, J. Brett, and D. Stern. 1993. Cytokine-mediated control of endothelial cell growth: interferon-α and interleukin-2 synergistically enhance basic fibroblast growth factor synthesis and induce release promoting cell growth in vitro and in vivo. J. Clin. Invest. 91:2504–2512.CrossRefGoogle Scholar
  5. Ensoli, B., S. Nakamura, Z.S. Salahuddin, P. Biberfeld, L. Larsson, B. Beaver, F. Wong-Staal, and R.C. Gallo. 1989. AIDS-Kaposi’s sarcoma-derived cells express cytokines wih autocrine and paracrine growth effects. Science. 243:223–226.PubMedCrossRefGoogle Scholar
  6. Ensoli, B., R. Gendelman, P. Markham, V. Fiorelli, S. Colombini, M. Raffeld, A. Cafaro, H.-K. Chang, J.N. Brady, and R.C. Gallo. 1994. Synergy between basic fibroblast growth factor and HIV-1 Tat protein in induction of Kaposi’s sarcoma. Nature. 371:674–680.PubMedCrossRefGoogle Scholar
  7. Enzinger, F.M., and Weiss, S.W. 1995. Soft tissue tumors. Mosby-Year Book, Inc. St. Louis, pp.658–669.Google Scholar
  8. Florkiewicz, R.Z., and A. Sommer. 1989. Human basic fibroblast growth factor gene encodes four polypeptides: three initiate translation from non-AUG codons. Proc. Natl. Acad. Sci. U.S.A. 86:3978–3981.PubMedCrossRefGoogle Scholar
  9. Good, D.J., P.J. Polverini, F. Rastinejad, M.M. LeBeau, R.S. Lemons, W.A. Frazier, and N.P. Bouck. 1990. 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.PubMedCrossRefGoogle Scholar
  10. Grant, D.S., K.-I. Tashiro, B. Segui-Real, Y. Yamada, G.R. Martin, and H.K. Kleinman. 1989. Two different laminin domains mediate the differentiation of human endothelial cells into capillary-like structures in vitro. Cell. 58:933–943.PubMedCrossRefGoogle Scholar
  11. Grinnell, F., and M.H. Bennett. 1981. Fibroblast adhesion on collagen substrata in the presence and absence of plasma fibronectin. J. Cell Sci. 48:19–34.PubMedGoogle Scholar
  12. Gross, J.L., W.F. Herblin, B.A. Dusak, P. Czerniak, M.D. Diamond, T. Sun, K. Eidsvoog, D.L. Dexter, and A. Yayon. 1993. Effects of modulation of basic fibroblast growth factor on tumor growth in vivo. J. Natl. Cancer Inst. 85:121–131.PubMedCrossRefGoogle Scholar
  13. Gualandris, A., D. Coltrini, L. Bergonzoni, A. Isacchi, S. Tenca, B. Ginelli, and M. Presta. 1993. The NH2-terminal extension of high molecular weight forms of basic fibroblast growth factor (bFGF) is not essential for the binding of bFGF to nuclear chromatin in transfected NIH 3T3 cells. Growth Factors. 8:49–60.PubMedCrossRefGoogle Scholar
  14. Gualandris, A., C. Urbinati, M. Rusnati, M. Ziehe, and M. Presta. 1994. Interaction of high molecular weight basic fibroblast growth factor (bFGF) with endothelium: biological activity and intracellular fate of human recombinant Mr 24,000 bFGF. J. Cell. Physiol. 161:149–159.PubMedCrossRefGoogle Scholar
  15. Itoh, H., M. Mukoyama, R.E. Pratt, and V.J. Dzau. 1992. Specific blockade of basic fibroblast growth factor gene expression in endothelial cells by antisense oligonucleotide. Biochem. Biophys. Res. Commun. 188:1205–1213.PubMedCrossRefGoogle Scholar
  16. Kennedy, A., R.N. Frank, L.B. Sotolongo, A. Das, and N.L. Zhang. 1990. Proliferative response and macromolecular synthesis by ocular cells cultured on extracellular matrix materials. Curr. Eye Res. 9:307–312.PubMedCrossRefGoogle Scholar
  17. Klagsbrun, M., and P.A. D’Amore. 1991. Regulators of angiogenesis. Annu. Rev. Physiol. 53:217–39.PubMedCrossRefGoogle Scholar
  18. Klein, S., F.G. Giancotti, M. Presta, S.M. Albelda, C.A. Buck, and D.B. Rifkin. 1993. Basic fibroblast growth factor modulates integrin expression in microvascular endothelial cells. Mol. Biol. Cell. 4: 973–982.PubMedGoogle Scholar
  19. Kleinman, H.K., M.L. McGarvey, J.R. Hassell, V.L. Star, F.B. Cannon, G.W. Laurie, and G.R. Martin. 1986. Basement membrane complexes with biological activity. Biochemistry. 25:312–318.PubMedCrossRefGoogle Scholar
  20. Mignatti, P., R. Tauboi, E. Robbins, and D.B. Rifkin. 1989. In vitro angiogenesis on the human amniotic membrane: requirement for basic fibroblast growth factor. J. Cell Biol. 108:671–682.PubMedCrossRefGoogle Scholar
  21. Mignatti, P., R. Mazzieri, and D.B. Rifkin. 1991. Expression of the urokinase receptor in vascular endothelial cells is stimulated by basic fibroblast growth factor. J. Cell Biol. 113:1193–1201.PubMedCrossRefGoogle Scholar
  22. Montesano, R., and L. Orci. 1985. Tumor-promoting phorbol esters induce angiogenesis in vitro. Cell. 42:469–477.PubMedCrossRefGoogle Scholar
  23. Montesano, R., J.-D. Vassalli, A. Baird, R. Guillemin, and L. Orci. 1986. Basic fibroblast growth factor induces angiogenesis in vitro. Proc. Natl. Acad. Sci. U.S.A. 83:7297–7301.PubMedCrossRefGoogle Scholar
  24. Ohtani, H., S. Nakamura, Y. Watanabe, T. Mizoi, T. Saku, and H. Nagura. 1993. Immunocytochemical localization of basic fibroblast growth factor in carcinomas and inflammatory lesions of the human digestive tract. Lab. Invest. 68:520–527.PubMedGoogle Scholar
  25. Passaniti, A., R.M. Taylor, R. Pili, Y. Guo, P.V. Long, J.A. Haney, R.R. Pauly, D.S. Grant, and G.R. Martin. 1992. A simple, quantitative method for assessing angiogenesis and antiangiogenic agents using reconstituted basement membrane, heparin, and fibroblast growth factor. Lab. Invest. 67:519–528.PubMedGoogle Scholar
  26. Pepper, M.S., and P. Meda. 1992. Basic fibroblast growth factor increases junctional communication and connexin 43 expression in microvascular endothelial cells. J. Cell. Physiol. 153:196–205.PubMedCrossRefGoogle Scholar
  27. Pepper, M.S., A.-P. Sappino, R. Stocklin, R. Montesano, L. Orci, and J.-D. Vassalli. 1993. Upregulation of urokinase receptor expression on migrating endothelial cells. J. Cell Biol. 122:673–684.PubMedCrossRefGoogle Scholar
  28. Peverali, F.A., S.J. Mandriota, P. Ciana, R. Marelli, P. Quax, D.B. Rifkin, G. Delia Valle, and P. Mignatti. 1994. Tumor cells secrete an angiogenic factor that stimulates basic fibroblast growth factor and urokinase expression in vascular endothelial cells. J. Cell. Physiol. 161:1–14.PubMedCrossRefGoogle Scholar
  29. Presta, M., J.A.M. Maier, M. Rusnati, and G. Ragnotti. 1989. Basic fibroblast growth factor: production, mitogenic response, and post-receptor signal transduction in cultured normal and transformed fetal bovine aortic endothelial cells. J. Cell. Physiol. 141:517–526.PubMedCrossRefGoogle Scholar
  30. Quarto, N., D. Talarico, A. Sommer, R. Florkiewicz, C. Basilico, and D.B. Rifkin. 1989. Transformation by basic fibroblast growth factor requires high levels of expression: comparison with transformation by hst/K-fgf. Oncogene Res. 5:101–110.PubMedGoogle Scholar
  31. Ribatti, D., C. Urbinati, B. Nico, M. Rusnati, L. Roncali, and M. Presta. 1995. Endogenous basic fibroblast growth factor in the vascularization of the chick embryo chorioallantoic membrane. Dev. Biol., in press.Google Scholar
  32. Rusnati, M., C. Urbinati, and M. Presta. 1993. Internalization of basic fibroblast growth factor (bFGF) in cultured endothelial cells: role of the low affinity heparin-like bFGF receptors. J. Cell. Physiol. 154:152–161.PubMedCrossRefGoogle Scholar
  33. Salahuddin, S.Z., S. Nakamura, P. Biberfeld, M.H. Kaplan, P.D. Markham, L. Larsson, and R.C. Gallo. 1988. Angiogenic properties of Kaposi’s sarcoma-derived cells after long-term culture in vitro. Science. 242:430–433.PubMedCrossRefGoogle Scholar
  34. Sato, Y., and D.B. Rifkin. 1988. Autocrine activities of basic fibroblast growth factor: regulation of endothelial cell movement, plasminogen activator synthesis, and DNA synthesis. J. Cell Biol. 107:1199–1205.PubMedCrossRefGoogle Scholar
  35. Schanper, H.W., D.S. Grant, W.G. Stetler-Stevenson, R. Fridman, G. D’Orazi, A.N. Murphy, R.E. Bird, M. Hoythya, T.R. Fuerst, D.L. French, J.P. Quigley, and H.K. Kleinman. 1993. Type IV collagenase(s) and TIMPs modulate endothelial cell morphogenesis in vitro. J. Cell. Physiol. 156:235–246CrossRefGoogle Scholar
  36. Schulze-Osthoff, K., W. Risau, E. Vollmer, and C. Sorg. 1990. In situ detection of basic fibroblast growth factor by highly specific antibodies. Am. J. Pathol. 137:85–92.PubMedGoogle Scholar
  37. Schweigerer, L., G. Neufeld, J. Friedman, J.A. Abraham, J.C. Fiddes, and D. Gospodarowicz. 1987. Capillary endothelial cells express basic fibroblast growth factor, a mitogen that promotes their own growth. Nature. 325:257–259.PubMedCrossRefGoogle Scholar
  38. Statuta, M., M.G. Ennas, G. Zamboni, F. Bonetti, M. Pea, F. Bernardello, A. Pozzi, M. Rusnati, A. Gualandris, and M. Presta. 1993. Basic fibroblast growth factor in human pheochromocytoma: a biochemical and immunohistochemical study. Int. J. Cancer. 53: 5–10.CrossRefGoogle Scholar
  39. Takahashi, J.A., H. Mori, M. Fukumoto, K. Igarashi, M. Jaye, Y. Oda, H. Kikuchi, and M. Hatanaka. 1990. Gene expression of fibroblast growth factors in human gliomas and meningiomas: demonstration of cellular source of basic fibroblast growth factor mRNA and peptide in tumor tissues. Proc. Natl. Acad. Sci. U.S.A.87:5710–5714.PubMedCrossRefGoogle Scholar
  40. Takahashi, K., J.B. Mulliken, H.P. Kozakewich, R.A. Rogers, J. Folkman, and R.A. Ezekowitz. 1994. Cellular markers that distinguish the phases of hemangioma during infancy and childhood. J. Clin. Invest. 93:2357–2364.PubMedCrossRefGoogle Scholar
  41. Taraboletti, G., D. Roberts, L.A. Liotta, and R. Giavazzi. 1990. Platelet thrombospondin modulates endothelial cell adhesion, motility, and growth: a potential angiogenesis regulatory factor. J. Cell Biol. 111:765–772.PubMedCrossRefGoogle Scholar
  42. Tsuboi, R., Y. Sato, and D.B. Rifkin. 1990. Correlation of cell migration, cell invasion, receptor number, proteinase production, and basic fibroblast growth factor levels in endothelial cells. J. Cell Biol. 110:511–517.PubMedCrossRefGoogle Scholar
  43. Vernon, R.B., T.F. Lane, J.C. Angello, and E.H. Sage. 1991. Adhesion, shape, proliferation, and gene expression of mouse Leydig cells are influenced by extracellular matrix in vitro. Biol. Reprod. 44:157–162.PubMedCrossRefGoogle Scholar
  44. Vernon, R.B., J.C. Angello, M.L. Iruela-Arispe, T.F. Lane, and E.H. Sage. 1992. Reorganization of basement membrane matrices by cellular traction promotes the formation of cellular networks in vitro. Lab. Invest. 66:536–547.PubMedGoogle Scholar
  45. Vlodavski, I., R. Friedman, R. Sullivan, J. Sasse, and M. Klagsbrun. 1987. Aortic endothelial cells synthesize basic fibroblast growth factor which remains cell associated and platelet-derived growth factor-like protein which is secreted. J. Cell. Physiol. 131:402–408.CrossRefGoogle Scholar
  46. Weich, H., N. Iberg, M. Klagsbrun, and J. Folkman. 1991. Transcriptional regulation of basic fibroblast growth factor gene expression in capillary endothelial cells. J. Cell. Biochem. 47:158–194.PubMedCrossRefGoogle Scholar
  47. Williams, R.L., W. Risau, A.-G. Zerwes, H. Drexler, A. Aguzzi, and E.F. Wagner. 1989. Endothelioma cells expressing the polyoma middle T oncogene induce hemangiomas by host cell recruitment. Cell. 57:1053–1063.PubMedCrossRefGoogle Scholar
  48. Xerri, L., J. Hassoun, J. Planchet, V. Guigou, J.J. Grobb, P. Pare, D. Birnbaum, and O. deLapeyriere. 1991. Fibroblast growth factor gene expression in AEDS-Kaposi’s sarcoma detected by in situ hybridization. Am. J. Pathol. 138:9–15.PubMedGoogle Scholar
  49. Zagzag, D., D.C. Miller, Y. Sato, D.B. Rifkin, and D.E. Burstein. 1990. Immunohistochemical localization of basic fibroblast growth factor in astrocytomas. Cancer Res. 50:7393–7398.PubMedGoogle Scholar
  50. Ziehe, M., G. Alessandri, and P.M. Gullino. 1989. Gangliosides promote the angiogenic response. Lab. Invest. 61:629–634.Google Scholar

Copyright information

© Plenum Press, New York 1996

Authors and Affiliations

  • Anna Gualandris
    • 1
  • Marco Rusnati
    • 1
  • Patrizia Dell’Era
    • 1
  • Daniela Coltrini
    • 1
  • Elena Tanghetti
    • 1
  • Emanuele Nelli
    • 1
  • Marco Presta
    • 1
  1. 1.Unit of General Pathology and Immunology, Department of Biomedical Sciences and BiotechnologyUniversity of BresciaBresciaItaly

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