Skip to main content
NCBI home page
Japanese Journal of Cancer Research : Gann logoLink to Japanese Journal of Cancer Research : Gann
. 1994 Jan;85(1):53–62. doi: 10.1111/j.1349-7006.1994.tb02886.x

Cooperative Roles of Hepatocyte Growth Factor and Plasminogen Activator in Tubular Morphogenesis by Human Microvascular Endothelial Cells

Akio Morimoto 1,✉, Katsuhiro Tada 1, Yoshifumi Nakayama 3, Kimitoshi Kohno 1, Seiji Naito 2, Mayumi Ono 3, Michihiko Kuwano 1,3
PMCID: PMC5919333  PMID: 7508907

Abstract

Epidermal growth factor (EGF) or transforming growth factor‐α (TGF‐α) stimulated cell migration, chemotaxis, and the expression of tissue‐type plasminogen activator (t‐PA) in human omental microvascular endothelial (HOME) cells. Hepatocyte growth factor (HGF) stimulated cell proliferation, but had a negligible stimulatory effect on cell migration, the expression of t‐PA and tube‐like formation into collagen gel in HOME cells. Basic fibroblast growth factor stimulated cell proliferation, cell migration, tubulogenesis and the expression of urokinase‐type plasminogen activator (u‐PA) in bovine aortic endothelial (BAE) cells. HOME and BAE cells had both high‐ and low‐affinity receptors for HGF. In BAE cells, u‐PA activity and tube‐like structures in collagen gel were induced in the presence of HGF alone. In contrast, in HOME cells, t‐PA activity and tube‐like structures were induced in the presence of TGF‐a alone, but not in the presence of HGF alone. However, we observed a marked induction of tube formation by HOME cells when both t‐PA and HGF were added simultaneously. In the model system for tumor angiogenesis, when HOME cells were co‐cultured with a renal cancer cell line, KPK13, tube‐like structures were induced in the presence of HGF: KPK13 cells expressed large amounts of t‐PA mRNA. Our present study suggested that HGF in concert with active t‐PA could be angiogenic in HOME cells.

Keywords: Hepatocyte growth factor, Plasminogen activator, Angiogenesis

Full Text

The Full Text of this article is available as a PDF (721.4 KB).

REFERENCES

  • 1. ) Gospodarowicz , D. , Bialecki , H. and Thakral , T. K.The angiogenic activity of the fibroblast and epidermal growth factor . Exp. Eye Res. , 28 , 501 – 514 ( 1979. ). [DOI] [PubMed] [Google Scholar]
  • 2. ) McAuslan , B. R. , Bender , V. , Reilly , W. and Moss , B. A.New functions of epidermal growth factor: stimulation of capillary endothelial cell migration and matrix dependent proliferation . Cell. Biol. Int. Rep. , 9 , 175 – 182 ( 1985. ). [DOI] [PubMed] [Google Scholar]
  • 3. ) Schreiber , A. B. , Winkler , M. E. and Derynck , R.Transforming growth factor‐alpha: a more potent angiogenic mediator than epidermal growth factor . Science , 232 , 1250 – 1253 ( 1986. ). [DOI] [PubMed] [Google Scholar]
  • 4. ) Moscatelli , D. , Presta , M. , Joseph , S. J. and Rifkin , D. B.Transformation of NIH 3T3 cells with basic fibroblast growth factor or the hst/K‐fgf oncogene causes down‐regulation of the fibroblast growth factor receptor: reversal of morphological transformation and restoration of receptor number by suramin . J. Cell. Physiol. , 129 , 273 – 276 ( 1986. ). 3021787 [Google Scholar]
  • 5. ) Rifkin , D. B. and Moscatelli , D.Recent developments in the cell biology of basic fibroblast growth factor . J. Cell Biol , 109 , 1 – 6 ( 1989. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6. ) Mawatari , M. , Kohno , K. , Mizoguchi , H. , Matsuda , T. , Aso , K. , van Damme , J. , Welgus , H. G. and Kuwano , M.Effects of tumor necrosis factor and epidermal growth factor on cell morphology, cell surface receptors, and the production of tissue inhibitor of metalloproteinases and IL‐6 in human microvascular endothelial cells . J. Immunol , 143 , 1619 – 1627 ( 1989. ). [PubMed] [Google Scholar]
  • 7. ) Mawatari , M. , Okamura , K. , Matsuda , T. , Hamanaka , R. , Mizoguchi , H. , Higashio , K. , Kohno , K. and Kuwano , M.Tumor necrosis factor and epidermal growth factor modulate migration of human microvascular endothelial cells and production of tissue‐type plasminogen activator and its inhibitor . Exp. Cell Res. , 192 , 574 – 580 ( 1991. ). [DOI] [PubMed] [Google Scholar]
  • 8. ) Matsuda , T. , Okamura , K. , Sato , Y. , Morimoto , A. , Ono , M. , Kohno , K. and Kuwano , M.Decreased response to epidermal growth factor during cellular senescence in cultured human microvascular endothelial cells . J. Cell. Physiol , 150 , 510 – 516 ( 1992. ). [DOI] [PubMed] [Google Scholar]
  • 9. ) Okamura , K. , Morimoto , A. , Hamanaka , R. , Ono , M. , Kohno , K. , Uchida , Y. and Kuwano , M.A model system for tumor angiogenesis: involvement of transforming growth factor‐α in tube formation of human micro‐vascular endothelial cells induced by esophageal cancer cells . Biochem. Biophys. Res, Commun. , 186 , 1471 – 1479 ( 1992. ). [DOI] [PubMed] [Google Scholar]
  • 10. ) Ono , M. , Okamura , K. , Nakayama , Y. , Tomita , M. , Sato , Y. , Komatsu , Y. and Kuwano , M.Induction of human microvascular endothelial tubular morphogenesis by human keratinocytes: involvement of transforming growth factor‐α . Biochem. Biophys. Res. Commun. , 189 , 601 – 609 ( 1992. ). [DOI] [PubMed] [Google Scholar]
  • 11. ) Sato , Y. , Okamura , K. , Morimoto , A. , Hamanaka , R. , Hamaguchi , K. , Shimada , T. , Ono , M. , Kohno , K. , Sakata , T. and Kuwano , M.Indispensable role of tissue‐type plasminogen activator in growth factor‐dependent tube formation of human microvascular endothelial cells in vitro . Exp. Cell Res. , 204 , 223 – 229 ( 1993. ). [DOI] [PubMed] [Google Scholar]
  • 12. ) Pepper , M. S. , Vassalli , J. D. , Montesano , R. and Orci , L.Urokinase‐type plasminogen activator is induced in migrating capillary endothelial cells . J. Biol. Chem. , 105 , 2535 – 2541 ( 1987. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13. ) Sato , Y. and Rifkin , D. B , Autocrine activities of basic fibroblast growth factor: regulation of endothelial cell movement, plasminogen activator synthesis, and DNA synthesis . J. Cell Biol. , 107 , 1199 – 1205 ( 1988. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14. ) Sato , Y. , Shimada , T. and Takaki , R.Autocrinological role of basic fibroblast growth factor on tube formation of vascular endothelial cells in vitro . Biochem. Biophys. Res. Commun. , 180 , 1098 – 1102 ( 1991. ). [DOI] [PubMed] [Google Scholar]
  • 15. ) Nakamura , T. , Nawa , K. , Ichihara , A. , Kaise , N. and Nishino , T.Purification and subunit structure of hepatocyte growth factor from rat platelets . FEBS Lett. , 224 , 311 – 316 ( 1987. ). [DOI] [PubMed] [Google Scholar]
  • 16. ) Nakamura , T. , Nishizawa , T. , Hagiya , M. , Seki , T. , Shimonishi , M. , Sugimura , A. , Tashiro , K. and Shimizu , S.Molecular cloning and expression of human hepatocyte growth factor . Nature , 342 , 440 – 443 ( 1989. ). [DOI] [PubMed] [Google Scholar]
  • 17. ) Gohda , E. , Tsubouchi , H. , Nakayama , H. , Hirono , S. , Sakuyama , O. , Takahashi , K. , Miyazaki , H. , Hashimoto , S. and Daikuhara , Y.Purification and partial characterization of hepatocyte growth factor from plasma of a patient with fulminant hepatic failure . J. Clin. Invest. , 81 , 414 – 419 ( 1988. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18. ) Matsumoto , K. , Tajima , H. and Nakamura , T.Hepatocyte growth factor is a potent stimulator of human melanocyte DNA synthesis and growth . Biochem. Biophys. Res. Commun. , 176 , 45 – 51 ( 1991. ). [DOI] [PubMed] [Google Scholar]
  • 19. ) Shima , N. , Itagaki , Y. , Nagao , M. , Yasuda , H. , Morinaga , T. and Higashio , K.A fibroblast‐derived tumor cytotoxic factor/F‐TCF (hepatocyte growth factor/HGF) has multiple functions in vitro . Cell Biol. Int. Rep. , 15 , 397 – 408 ( 1991. ). [DOI] [PubMed] [Google Scholar]
  • 20. ) Miyazawa , K. , Tsubouchi , H. , Naka , D. , Takahashi , K. , Okigaki , M. , Arakaki , N. , Nakayama , H. , Hirono , S. , Sakiyama , O. , Takahashi , K. , Gohda , E. , Daikuhara , Y. and Kitamura , N.Molecular cloning and sequence analysis of cDNA for human hepatocyte growth factor . Biochem. Biophys. Res. Commun. , 163 , 967 – 973 ( 1989. ). [DOI] [PubMed] [Google Scholar]
  • 21. ) Zarnegar , R. , Muga , S. , Rahija , R. and Michalopoulos , G.Molecular cloning and sequence analysis of cDNA for human hepatocyte growth factor . Proc. Natl. Acad. Sci. USA , 87 , 1252 – 1256 ( 1990. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22. ) Bottaro , D. P. , Rubin , J. S. , Faletto , D. L. , Chan , A. M. , Kmiecik , T. E. , Vande Woude , G. F. and Aaronson , S. A.Identification of the hepatocyte growth factor receptor as the c‐met proto‐oncogene product . Science , 251 , 802 – 804 ( 1991. ). [DOI] [PubMed] [Google Scholar]
  • 23. ) Naldini , L. , Vigna , E. , Narsimhan , R. P. , Gaudino , G. , Zarnegar , R. , Michalopoulos , G. K. and Comoglio , P. M.Hepatocyte growth factor (HGF) stimulates the tyrosine kinase activity of the receptor encoded by the proto‐oncogene c‐MET . Oncogene , 6 , 501 – 504 ( 1991. ). [PubMed] [Google Scholar]
  • 24. ) Higuchi , O. , Mizuno , K. , Vande Woude , G. F. and Nakamura , T.Expression of c‐met proto‐oncogene in COS cells induces the signal transducing high‐affinity receptor for hepatocyte growth factor . FEBS Lett. , 301 , 282 – 286 ( 1992. ). [DOI] [PubMed] [Google Scholar]
  • 25. ) Cooper , C. S. , Park , M. , Blair , D. G. , Tainsky , M. A. , Huebner , K. , Croce , C. M. and Vande Woude , G. F.Molecular cloning of a new transforming gene from a chemically transformed human cell line . Nature , 311 , 29 – 33 ( 1984. ). [DOI] [PubMed] [Google Scholar]
  • 26. ) Iyer , A. , Kmiecik , T. E. , Park , M. , Daar , I. , Blair , D. , Dunn , K. J. , Sutrave , P. , Ihle , J. N. , Bodescot , M. and Vande Woude , G. F.Structure, tissue‐specific expression, and transforming activity of the mouse met proto‐oncogene . Cell Growth Diff. , 1 , 87 – 95 ( 1990. ). [PubMed] [Google Scholar]
  • 27. ) Montesano , R. , Schaller , G. and Orci , L.Induction of epithelial tubular morphogenesis in vitro by fibroblast‐derived soluble factors . Cell , 66 , 697 – 711 ( 1991. ). [DOI] [PubMed] [Google Scholar]
  • 28. ) Montesano , R. , Matsumoto , K. , Nakamura , T. and Orci , L.Identification of a fibroblast‐derived epithelial morphogen as hepatocyte growth factor . Cell , 67 , 901 – 908 ( 1991. ). [DOI] [PubMed] [Google Scholar]
  • 29. ) Pepper , M. S. , Matsumoto , K. , Nakamura , T. , Orci , L. and Montesano , R.Hepatocyte growth factor increases urokinase‐type plasminogen activator (u‐PA) and u‐PA receptor expression in Madin‐Darby canine kidney epithelial cells . J. Biol. Chem. , 267 , 20493 – 20496 ( 1992. ). [PubMed] [Google Scholar]
  • 30. ) Rubin , J. S. , Chan , A. M. , Bottaro , D. P. , Burgess , W. H. , Taylor , W. G. , Cech , A. C. , Hirschfield , D. W. , Wong , J. , Miki , T. , Finch , P. W. and Aaronson , S. A.A broad‐spectrum human lung fibroblast‐derived mitogen is a variant of hepatocyte growth factor . Proc. Natl. Acad. Sci. USA , 88 , 415 – 419 ( 1991. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31. ) Kan , M. , Zhang , G. H. , Zarnegar , R. , Michalopoulos , G. , Myoken , Y. , McKeehan , W. L. and Stevens , J. I.Hepatocyte growth factor/hepatopoietin A stimulates the growth of rat kidney proximal tubule epithelial cells (RPTE), rat nonparenchymal liver cells, human melanoma cells, mouse keratinocytes and stimulates anchorage‐independent growth of SV‐40 transformed RPTE . Biochem. Biophys. Res. Commun. , 174 , 331 – 337 ( 1991. ). [DOI] [PubMed] [Google Scholar]
  • 32. ) Rosen , E. M. , Grant , D. , Kleinman , H. , Jaken , S. , Donovan , M. A. , Setter , E. , Luckett , P. M. , Carley , W. , Bhargava , M. and Goldberg , I. D.Scatter factor stimulates migration of vascular endothelium and capillary‐like tube formation . In “ Cell Motility Factors, ” pp. 76 – 88 ( 1991. ). Birkhauser‐Verlag; , Basel . [DOI] [PubMed] [Google Scholar]
  • 33. ) Bussolino , F. , Di Renzo , M. F. , Ziche , M. , Bocchietto , E. , Olivero , M. , Naldini , L. , Gaudino , G. , Tamagnone , L. , Coffer , A. and Comoglio , P. M.Hepatocyte growth factor is a potent angiogenic factor which stimulates endothelial cell motility and growth . J. Cell Biol. , 119 , 629 – 641 ( 1992. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34. ) Morimoto , A. , Okamura , K. , Hamanaka , R. , Sato , Y. , Shima , N. , Higashio , K. and Kuwano , M.Hepatocyte growth factor modulates migration and proliferation of human microvascular endothelial cells in culture . Biochem. Biophys, Res. Commun. , 179 , 1042 – 1049 ( 1991. ). [DOI] [PubMed] [Google Scholar]
  • 35. ) Okamura , K. , Sato , Y. , Matsuda , T. , Hamanaka , R. , Ono , M. , Kohno , K. and Kuwano , M.Endogenous basic fibroblast growth factor‐dependent induction of collagenase and interleukin‐6 in tumor necrosis factor‐treated human microvascular endothelial cells . J. Biol Chem. , 266 , 19162 – 19165 ( 1991. ). [PubMed] [Google Scholar]
  • 36. ) Abe , T. , Okamura , K. , Ono , M. , Kohno , K. , Mori , T. , Hori , S. and Kuwano , M.Induction of vascular endothelial tubular morphogenesis by human glioma cells: a model system for tumor angiogenesis . J. Clin. Invest. , 92 , 54 – 61 ( 1993. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37. ) Naito , S. , Kanamori , T. , Hisano , S. , Tanaka , K. , Momose , S. and Kamata , N.Human renal cell carcinoma: establishment and characterization of two new cell lines . J. Urol. , 128 , 1117 – 1121 ( 1982. ). [DOI] [PubMed] [Google Scholar]
  • 38. ) Nakayama , Y. , Kohno , K. , Nomura , Y. , Naito , S. , Ono , M. , Shimizu , K. , Osato , K. and Kuwano , M.Enhanced invasive activity and decreased expression of tissue inhibitors of metalloproteinases by hepatocyte growth factor in human renal cancer cells . Cancer J. , 6 , 213 – 219 ( 1993. ). [Google Scholar]
  • 39. ) Shima , N. , Nagao , M. , Ogaki , F. , Tsuda , E. , Murakami , A. and Higashio , K.Tumor cytotoxic factor/hepatocyte growth factor from human fibroblasts: cloning of its cDNA, purification and characterization of recombinant protein . Biochem. Biophys. Res. Commun. , 180 , 1151 – 1158 ( 1991. ). [DOI] [PubMed] [Google Scholar]
  • 40. ) Ono , M. , Kuwano , M. and Kung , H. F.Malignant transformation of mouse BALB/3T3 cells by polyoma middle T antigen requires epidermal growth factor receptor expression . Cell Growth Differ. , 2 , 317 – 322 ( 1991. ). [PubMed] [Google Scholar]
  • 41. ) Ono , M. , Nakayama , Y. , Princler , G. , Gopas , J. , Kung , H. F. and Kuwano , M.Polyoma middle T antigen or v‐src desensitizes human epidermal growth factor receptor function and interference by a monensin‐resistant mutation in mouse Balb/3T3 cells . Exp. Cell Res. , 203 , 456 – 465 ( 1992. ). [DOI] [PubMed] [Google Scholar]
  • 42. ) Yoshitake , S. , Kato , H. , Hashimoto , A.Ikeda , Y. and Kuwada , M.Characterization of various forms of modified human tissue plasminogen activators . Thromb. Haemostasis , 62 , 542 ( 1989. ). [Google Scholar]
  • 43. ) Fisher , R. , Waller , E. K. , Grossi , G. , Thompson , D. , Tizard , R. and Schleuning , W. D.Isolation and characterization of the human tissue‐type plasminogen activator structural gene including its 5′ flanking region . J. Biol. Chem. , 260 , 11223 – 11230 ( 1985. ). [PubMed] [Google Scholar]
  • 44. ) Schleef , R. R. , Bevilacqua , M. P. , Sawdey , M. , Gimbrone , M. A. and Loskutoff , D. J.Cytokine activation of vascular endothelium . J. Biol. Chem. , 263 , 5797 – 5803 ( 1988. ). [PubMed] [Google Scholar]
  • 45. ) Park , M. , Dean , M. , Kaul , K. , Braun , M. J. , Gonda , M. A. and Vande Woude , G. F.Sequence of MET proto‐oncogene cDNA has features characteristic of the tyrosine kinase family of growth‐factor receptors . Proc. Natl. Acad. Sci. USA , 84 , 6379 – 6383 ( 1987. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46. ) Hamanaka , R. , Kohno , K. , Seguchi , T. , Okamura , K. , Morimoto , A. , Ono , M. , Ogata , J. and Kuwano , M.Induction of low density lipoprotein receptor and a transcription factor SP‐1 by tumor necrosis factor in human microvascular endothelial cells . J. Biol, Chem. , 276 , 13160 – 13165 ( 1992. ). [PubMed] [Google Scholar]
  • 47. ) Mizoguchi , H. , Uchiumi , K. , Ono , M. , Kohno , K. and Kuwano , M.Enhanced production of tissue‐type plasminogen activator by estradiol in a novel type variant of human breast cancer MCF‐7 cell line . Biochim. Biophys. Acta , 1052 , 475 – 482 ( 1990. ). [DOI] [PubMed] [Google Scholar]
  • 48. ) Gonzatti‐Haces , M. , Seth , A. , Park , M. , Copeland , T. , Oroszlan , S. and Vande Woude , G. F.Characterization of the TPR‐MET oncogene p65 and the MET protooncogene p140 protein‐tyrosine kinases . Proc, Natl. Acad. Sci. USA , 85 , 21 – 25 ( 1988. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 49. ) Giordano , S. , Ponzetto , C , Di Renzo , M. F. , Cooper , C. S. and Comoglio , P. M.Tyrosine kinase receptor indistinguishable from the c‐met protein . Nature , 339 , 155 – 156 ( 1989. ). [DOI] [PubMed] [Google Scholar]
  • 50. ) Montesano , R. , Vassalli , J. D. , Baird , A. , Guillemin , R. and Orci , L.Basic fibroblast growth factor induces angiogenesis in vitro . Proc. Natl. Acad. Sci. USA , 83 , 7297 – 7301 ( 1986. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 51. ) Mignatti , P. , Tsuboi , R. , Robbins , E. and Rifkin , D. B.In vitro angiogenesis on the human amniotic membrane: requirement for basic fibroblast growth factor‐induced proteinases . J. Cell Biol. , 108 , 671 – 682 ( 1989. ). [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Japanese Journal of Cancer Research : Gann are provided here courtesy of Wiley

RESOURCES