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. 2000 Jan 18;82(2):385–391. doi: 10.1054/bjoc.1999.0931

Identification of angiogenic properties of insulin-like growth factor II in in vitro angiogenesis models

O H Lee 1, S K Bae 1, M H Bae 1, Y M Lee 1, E J Moon 1, H J Cha 1, Y G Kwon 2, K W Kim 1
PMCID: PMC2363289  PMID: 10646893

Abstract

Insulin-like growth factor II (IGF-II), highly expressed in a number of human tumours, has been recently known to promote neovascularization in vivo. Yet, the detailed mechanism by which IGF-II induces angiogenesis has not been well defined. In the present study, we explored an angiogenic activity of IGF-II in in vitro angiogenesis model. Human umbilical vein endothelial cells (HUVECs) treated with IGF-II rapidly aligned and formed a capillary-like network on Matrigel. In chemotaxis assay, IGF-II remarkably increased migration of HUVECs. A rapid and transient activation of p38 mitogen-activated protein kinase (p38 MAPK) and p125 focal adhesion kinase (p125FAK) phosphorylation was detected in HUVECs exposed to IGF-II. IGF-II also stimulated invasion of HUVECs through a polycarbonate filter coated with Matrigel. Quantitative gelatin-based zymography identified that matrix metalloproteinase-2 (MMP-2) activity generated from HUVECs was increased by IGF-II. This induction of MMP-2 activity was correlated with Northern blot analysis, showing in HUVECs that IGF-II increased the expression of MMP-2 mRNA, while it did not affect that of TIMP-2, a tissue inhibitor of MMP-2. These results provide the evidence that IGF-II directly induces angiogenesis by stimulating migration and morphological differentiation of endothelial cells, and suggest that IGF-II may play a crucial role in the progression of tumorigenesis by promoting the deleterious neovascularization. © 2000 Cancer Research Campaign

Keywords: insulin-like growth factor II, tube formation, migration, invasion, HUVECs

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Selected References

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  1. Abedi H., Zachary I. Vascular endothelial growth factor stimulates tyrosine phosphorylation and recruitment to new focal adhesions of focal adhesion kinase and paxillin in endothelial cells. J Biol Chem. 1997 Jun 13;272(24):15442–15451. doi: 10.1074/jbc.272.24.15442. [DOI] [PubMed] [Google Scholar]
  2. Albini A., Barillari G., Benelli R., Gallo R. C., Ensoli B. Angiogenic properties of human immunodeficiency virus type 1 Tat protein. Proc Natl Acad Sci U S A. 1995 May 23;92(11):4838–4842. doi: 10.1073/pnas.92.11.4838. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Albini A., Iwamoto Y., Kleinman H. K., Martin G. R., Aaronson S. A., Kozlowski J. M., McEwan R. N. A rapid in vitro assay for quantitating the invasive potential of tumor cells. Cancer Res. 1987 Jun 15;47(12):3239–3245. [PubMed] [Google Scholar]
  4. Bar R. S., Siddle K., Dolash S., Boes M., Dake B. Actions of insulin and insulinlike growth factors I and II in cultured microvessel endothelial cells from bovine adipose tissue. Metabolism. 1988 Aug;37(8):714–720. doi: 10.1016/0026-0495(88)90003-0. [DOI] [PubMed] [Google Scholar]
  5. Bowsher R. R., Lee W. H., Apathy J. M., O'Brien P. J., Ferguson A. L., Henry D. P. Measurement of insulin-like growth factor-II in physiological fluids and tissues. I. An improved extraction procedure and radioimmunoassay for human and rat fluids. Endocrinology. 1991 Feb;128(2):805–814. doi: 10.1210/endo-128-2-805. [DOI] [PubMed] [Google Scholar]
  6. Cohick W. S., Clemmons D. R. The insulin-like growth factors. Annu Rev Physiol. 1993;55:131–153. doi: 10.1146/annurev.ph.55.030193.001023. [DOI] [PubMed] [Google Scholar]
  7. Cullen K. J., Smith H. S., Hill S., Rosen N., Lippman M. E. Growth factor messenger RNA expression by human breast fibroblasts from benign and malignant lesions. Cancer Res. 1991 Sep 15;51(18):4978–4985. [PubMed] [Google Scholar]
  8. Daughaday W. H. The possible autocrine/paracrine and endocrine roles of insulin-like growth factors of human tumors. Endocrinology. 1990 Jul;127(1):1–4. doi: 10.1210/endo-127-1-1. [DOI] [PubMed] [Google Scholar]
  9. DeChiara T. M., Efstratiadis A., Robertson E. J. A growth-deficiency phenotype in heterozygous mice carrying an insulin-like growth factor II gene disrupted by targeting. Nature. 1990 May 3;345(6270):78–80. doi: 10.1038/345078a0. [DOI] [PubMed] [Google Scholar]
  10. Folkman J. Tumor angiogenesis. Adv Cancer Res. 1985;43:175–203. doi: 10.1016/s0065-230x(08)60946-x. [DOI] [PubMed] [Google Scholar]
  11. Groskopf J. C., Syu L. J., Saltiel A. R., Linzer D. I. Proliferin induces endothelial cell chemotaxis through a G protein-coupled, mitogen-activated protein kinase-dependent pathway. Endocrinology. 1997 Jul;138(7):2835–2840. doi: 10.1210/endo.138.7.5276. [DOI] [PubMed] [Google Scholar]
  12. Hanahan D., Folkman J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell. 1996 Aug 9;86(3):353–364. doi: 10.1016/s0092-8674(00)80108-7. [DOI] [PubMed] [Google Scholar]
  13. Hanemaaijer R., Koolwijk P., le Clercq L., de Vree W. J., van Hinsbergh V. W. Regulation of matrix metalloproteinase expression in human vein and microvascular endothelial cells. Effects of tumour necrosis factor alpha, interleukin 1 and phorbol ester. Biochem J. 1993 Dec 15;296(Pt 3):803–809. doi: 10.1042/bj2960803. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Herron G. S., Banda M. J., Clark E. J., Gavrilovic J., Werb Z. Secretion of metalloproteinases by stimulated capillary endothelial cells. II. Expression of collagenase and stromelysin activities is regulated by endogenous inhibitors. J Biol Chem. 1986 Feb 25;261(6):2814–2818. [PubMed] [Google Scholar]
  15. Kim K. W., Bae S. K., Lee O. H., Bae M. H., Lee M. J., Park B. C. Insulin-like growth factor II induced by hypoxia may contribute to angiogenesis of human hepatocellular carcinoma. Cancer Res. 1998 Jan 15;58(2):348–351. [PubMed] [Google Scholar]
  16. Kraft A., Reid L. M., Zvibel I. Suramin inhibits growth and yet promotes insulin-like growth factor II expression in HepG2 cells. Cancer Res. 1993 Feb 1;53(3):652–657. [PubMed] [Google Scholar]
  17. Matrisian L. M. The matrix-degrading metalloproteinases. Bioessays. 1992 Jul;14(7):455–463. doi: 10.1002/bies.950140705. [DOI] [PubMed] [Google Scholar]
  18. Minniti C. P., Tsokos M., Newton W. A., Jr, Helman L. J. Specific expression of insulin-like growth factor-II in rhabdomyosarcoma tumor cells. Am J Clin Pathol. 1994 Feb;101(2):198–203. doi: 10.1093/ajcp/101.2.198. [DOI] [PubMed] [Google Scholar]
  19. Nishimoto I. The IGF-II receptor system: a G protein-linked mechanism. Mol Reprod Dev. 1993 Aug;35(4):398–407. doi: 10.1002/mrd.1080350414. [DOI] [PubMed] [Google Scholar]
  20. Pieces of eight: bioactive fragments of extracellular proteins as regulators of angiogenesis. Trends Cell Biol. 1997 May;7(5):182–186. doi: 10.1016/S0962-8924(97)01037-4. [DOI] [PubMed] [Google Scholar]
  21. Reeve A. E., Eccles M. R., Wilkins R. J., Bell G. I., Millow L. J. Expression of insulin-like growth factor-II transcripts in Wilms' tumour. Nature. 1985 Sep 19;317(6034):258–260. doi: 10.1038/317258a0. [DOI] [PubMed] [Google Scholar]
  22. Rousseau S., Houle F., Landry J., Huot J. p38 MAP kinase activation by vascular endothelial growth factor mediates actin reorganization and cell migration in human endothelial cells. Oncogene. 1997 Oct;15(18):2169–2177. doi: 10.1038/sj.onc.1201380. [DOI] [PubMed] [Google Scholar]
  23. Stewart C. E., Rotwein P. Growth, differentiation, and survival: multiple physiological functions for insulin-like growth factors. Physiol Rev. 1996 Oct;76(4):1005–1026. doi: 10.1152/physrev.1996.76.4.1005. [DOI] [PubMed] [Google Scholar]
  24. Storckenfeldt L., Schofield P. N., Engström W. Stimulatory effect of insulin like growth factor II on DNA synthesis in the human embryonic cornea. Cell Biol Int Rep. 1991 Dec;15(12):1217–1223. doi: 10.1016/0309-1651(91)90093-x. [DOI] [PubMed] [Google Scholar]
  25. Sullivan K. A., Castle V. P., Hanash S. M., Feldman E. L. Insulin-like growth factor II in the pathogenesis of human neuroblastoma. Am J Pathol. 1995 Dec;147(6):1790–1798. [PMC free article] [PubMed] [Google Scholar]
  26. Volpert O., Jackson D., Bouck N., Linzer D. I. The insulin-like growth factor II/mannose 6-phosphate receptor is required for proliferin-induced angiogenesis. Endocrinology. 1996 Sep;137(9):3871–3876. doi: 10.1210/endo.137.9.8756559. [DOI] [PubMed] [Google Scholar]

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