Skip to main content
Journal of Cellular and Molecular Medicine logoLink to Journal of Cellular and Molecular Medicine
. 2007 May 1;4(4):262–269. doi: 10.1111/j.1582-4934.2000.tb00125.x

New molecular mediators in tumor angiogenesis

W‐D Beecken 1,, W Kramer 1, D Jonas 1
PMCID: PMC6517823  PMID: 12067460

Abstract

Angiogenesis is essential for tumor growth and progression. It has been demonstrated that tumor growth beyond a size 1 to 2 mm3 requires the induction of new vessels. Angiogenesis is regulated by several endogenous stimulators and inhibitors of endothelial cell migration, proliferation and tube formation. Under physiological conditions these mediators of endothelial cell growth are in balance and vessel growth is limited. In fact, within the angiogenic balance endothelial cell turnover is sufficient to maintain a functional vascular wall but does not allow vessel growth. Tumor growth an progression has successfully been correlated to the serum concentration of angiogenic mediators. Furthermore, the vascular density of tumor tissues could be correlated to the clinical course of the disease in several tumor entities. Within the last years several new mediators of endothelial cell growth have been isolated e.g. angiopoietin 1, angiopoietin 2, midkine, pleiotropin, leptin and maspin. In this review we discuss the mechanisms leading to tumor angiogenesis and describe some of the newer mediators of endothelial cell stimulation and inhibition.

Keywords: tumor angiogenesis, angiopoietins, leptin, midkine, pleiotropin, maspin

References

  • 1. Warran B. A., The vascular morphology of tumors In: Peterson H. I. editor, Tumor blood circulation: Angiogenesis, vascular morphology and blood flow of experimental human tumors. CRC Press; 1979, Miami , FL pp. 1–47. [Google Scholar]
  • 2. Coman D. R., Sheldon W. F., The significance of hyperemia around tumor implants, Am. J. Pathol., 22:821, 1946. [PubMed] [Google Scholar]
  • 3. Ide A. G., Baker N. H., Warren S. L., Vascularization of the Brown‐Peatce rabbit epithelioma transplant as seen in the transparent ear chamber, Am. J. Roentgenol., 42:891, 1939. [Google Scholar]
  • 4. Hanahan D., Weinberg R. A., The hallmarks of cancer, Cell, 100:57, 2000. [DOI] [PubMed] [Google Scholar]
  • 5. Folkman J., Tumor angiogenesis: therapeutic implications, N. Engl. J. Med., 285:1182, 1971. [DOI] [PubMed] [Google Scholar]
  • 6. Webpage of the National Cancer Institute , http://www.nci.nih.gov.
  • 7. Hobson B., Denekamp J., Endothelial proliferation in tumors and normal tissues: continouus labeling studies, Br. J. Cancer, 49:405, 1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8. Auerbach W., Auerbach R., Angiogenesis inhibition: a review, Pharmacol. Ther:, 63:265, 1994. [DOI] [PubMed] [Google Scholar]
  • 9. Hanahan D., Folkman J., Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis, Cell, 86:353, 1996. [DOI] [PubMed] [Google Scholar]
  • 10. Weinstat‐Saslow D., Steeg P. S., Angiogenesis and colonization in the tumor metastatic process: basic and applied advances, FASEB J., 8:401, 1994. [DOI] [PubMed] [Google Scholar]
  • 11. Weidner N., Semple J. P., Welch W. R., Folkman J., Tumor angiogenesis correlates with metastasis in invasive breast carcinoma, N. Engl. J. Med., 324:1, 1991. [DOI] [PubMed] [Google Scholar]
  • 12. Weidner N., Carroll P. R., Flax J., Blumenfeld W., Folkman J., Tumor angiogenesis correlates with metastasis in invasive prostate carcinoma, Am. J. Pathol., 143:401, 1993. [PMC free article] [PubMed] [Google Scholar]
  • 13. Fontanini G., Lucchi M., Vignati S., Mussi A., Ciardiello F., DeLaurentiis M., De Placido S., Basolo F., Angeletti C. A., Bevilacqua G., Angiogenesis as a prognostic indicator of survival in non‐small cell lung carcinoma: a prospective study, J. Natl. Cancer Inst., 89:881, 1997. [DOI] [PubMed] [Google Scholar]
  • 14. Lindmark G., Gerdin B, Sundberg C, Pahlman L., Bergstrom R., Glimelius B., Prognostic significance of microvascular count in colorectal cancer, J. Clin. Oncol., 14:461, 1996. [DOI] [PubMed] [Google Scholar]
  • 15. Srivastava A., Laidler P., Davies R. P., Horfan K., The prognostic significance of tumor vasclarity in intermediate‐thickness (0. 76‐4.0 mm) skin melanoma. A quantitative histologic study, Am. J. Pathol., 133:419, 1988. [PMC free article] [PubMed] [Google Scholar]
  • 16. Gimbrone M. A., Cotran R., Leapman S., Folkman J., Tumor growth and neovascularization: an experimental model using rabbit cornea, J. Natl. Cancer Inst., 52:413, 1974. [DOI] [PubMed] [Google Scholar]
  • 17. Campbell S. C., Volpert O. V., Ivanovich M., Bouck N. P., Molecular mediators of angiogenesis in bladder cancer, Cancer Res., 56:1298, 1998. [PubMed] [Google Scholar]
  • 18. Loncaster J. A., Cooper R. A., Logue J. P., Davidson S. E., Hunter R. D., West C. M., Vascular endothelial growth factor (VEGF) expression is a prognostic factor for radiotherapy outcome in advanced carcinoma of the cervix, Br. J. Cancer, 83:620, 2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19. Shen G. H., Ghazizadeh M., Kawanami O., Shimizu H., Jin E., Araki T., Sugisaki Y., Prognostic significance of vascular endothelial growth factor expression in human ovarian carcinoma, Br. J. Cancer, 83:196, 2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20. Mineta H., Miura K., Ogino T., Takebayashi S., Misawa K., Ueda Y., Suzuki I., Dictor M., Borg A., Wennerberg J., Prognostic value of vascular endothelial growth factor (VEGF) in head and neck squamous cell carcinoma, Br. J. Cancer, 83:775, 2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21. Lee J., Gray A., Yuan J., Luoh S. M., Avraham H., Wood W. I., Vascular endothelial growth factor‐related protein: a ligand and specific activator of the tyrosine kinase receptor Flt4, Proc. Natl. Acad. Sci., 93:1988, 1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22. Borg J. P., DeLapeyriere O., Noguchi T., Rottapel R., Dubreuil P., Birnbaum D., Biochemical characterization of two isoforms of FLT4, a VEGF receptor‐related tyrosine kinase, Oncogene, 10:973, 1995. [PubMed] [Google Scholar]
  • 23. Dumont D. J., Yamaguchi T. P., Conlon R. A., Rossant J., Breitman M. L., Tek, novel tyrosine kinase gene located on mouse chromosome, is expressed in endothelial cells and their presumptive precursor, Oncogene, 7:1471, 1992. [PubMed] [Google Scholar]
  • 24. Puri M. C., Rossant J., Alitalo K., Bernstein A., Partanen J., The receptor tyrosine kinase TIE is required for intergity and survival of vascular endothelial cells, EMBO J., 14:5884, 1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25. Davis S., Aldrich T. H., Jones P. F., Acheson A., Compton D. L., Jain V., Ryan T. E., Bruno J., Radziejewski C., Maisonpierre P. C., Yancopoulos G. D., Isolation of angiopoietin‐1, a ligand for the TIE2 receptor, by secretiontrap expression cloning [see comments], Cell, 87:1161, 1996. [DOI] [PubMed] [Google Scholar]
  • 26. Koblizek T. I., Weiss C., Yancopoulos G. D., Deutsch U., Risau W., Angiopoietin‐1 induces sprouting angiogenesis in vitro, Curr. Biol., 8:529, 1998. [DOI] [PubMed] [Google Scholar]
  • 27. Thurston G., Rudge J. S., Ioffe E., Zhou H., Ross L., Croll S. D., Glazer N., Holash J., McDonald D. M., Yancopoulos G. D., Angiopoietin‐1 protects the adult vasculature against plasma leakage, Nat. Med., 6:460, 2000. [DOI] [PubMed] [Google Scholar]
  • 28. Gamble J. R., Drew J., Trezise L., Underwood A., Parsons M., Kasminkas L., Rudge J., Yancopoulos G., Vadas M. A., Angiopietin‐1 is an antipermeability and anti‐inflammatory agent In vitro and targets cell junctions [In Process Ciation], Circ. Res., 87:603, 2000. [DOI] [PubMed] [Google Scholar]
  • 29. Willam C., Koehne P., Jurgensen J. S., Grafe M., Wagner K. D., Bachmann S., Frei U., Eckardt K. U., Tie2 receptor expression is stimulated by hypoxia and proinflammatory cytokines in human endothelial cells, Circ. Res., 87:370, 2000. [DOI] [PubMed] [Google Scholar]
  • 30. Takahama M., Tsutsumi M., Tsujiuchi T., Nezu K., Kushibe K., Taniguchi S., Kotake Y., Konishi Y., Enhanced expression of Tie2, its ligand angiopoietin‐1, vascular endothelial growth factor, and CD31 in human nonsmall cell lung carcinomas, Clin. Cancer Res., 5:2506, 1999. [PubMed] [Google Scholar]
  • 31. Maisonpierre P. C., Suri C., Jones P. F., Bartunkova S., Wiegand S. J., Radziejewski C., Compton D., McClain J., Aldrich T. H., Papadopoulos N., Daly T. J., Davis S., Sato T. N., Yancopoulos G. D., Angiopoietin‐2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis [see comments], Science, 277:55, 1997. [DOI] [PubMed] [Google Scholar]
  • 32. Mandriota, S. J. , Pepper M. S., Regulation of angiopoietin‐2 mRNA levels in bovine microvascular endothelial cells by cytokines and hypoxia, Circ. Res., 83:852, 1998. [DOI] [PubMed] [Google Scholar]
  • 33. Holash J., Wiegand S. J., Yancopoulos G. D., New model of tumor angiogenesis: dynamic balance between vessel regression and growth mediated by angiopoietins and VEGF, Oncogene, 18:5356, 1999. [DOI] [PubMed] [Google Scholar]
  • 34. Holash J., Maisonpierre P. C., Compton D., Boland P., Alexander C. R., Zagzag D., Yancopoulos G. D., Wiegand S. J., Vessel cooption, regression, and growth in tumors mediated by angiopoietins and VEGF, Science, 284:1994, 1999. [DOI] [PubMed] [Google Scholar]
  • 35. Wong M. P., Chan S. Y., Fu K. H., Leung S. Y., Cheung N., Yuen S. T., Chung L. P., The angiopoietins, tie2 and vascular endothelial growth factor are differentially expressed in the transformation of normal lung to non‐small cell lung carcinomas, Lung Cancer, 29:11, 2000. [DOI] [PubMed] [Google Scholar]
  • 36. Tanaka S., Mori M., Sakamoto Y., Makuuchi M., Sugimachi K., Wands J. R., Biologic significance of angiopoietin‐2 expression in human hepatocellular carcinoma, J. Clin. Invest., 103:341, 1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37. Yoshida Y., Oshika Y., Fukushima Y., Tokunaga T., Hatanaka H., Kijima H., Yamazaki H., Ueyama Y., Tamaoki N., Miura S., Nakamura M., Expression of angiostatic factors in colorectal cancer, Int. J. Oncol., 15:1221, 1999. [DOI] [PubMed] [Google Scholar]
  • 38. Carter W. B., Ward M. D., HER2 regulatory control of angiopoietin‐2 in breast cancer, Surgery, 128:153, 2000. [DOI] [PubMed] [Google Scholar]
  • 39. Kim I., Kim J. H., Ryu Y. S., Jung S. H., Nah J. J., Koh G. Y., Characterization and expression of a novel alternatively spliced human angiopoietin‐2, J. Biol. Chem., 275:18550, 2000. [DOI] [PubMed] [Google Scholar]
  • 40. Huang Y. Q., Li J. J., Karpatkin S., Identification of a family of alternatively spliced mRNA species of angiopoietin‐1, Blood, 95:1993, 2000. [PubMed] [Google Scholar]
  • 41. Pelleymounter M., Cullen M., Baker M., Hecht R., Winters D., Boone T., Collins F., Effects of the obese gene product on body weight regulation in ob/ob mice, Science, 269:540, 1995. [DOI] [PubMed] [Google Scholar]
  • 42. Henson M. C., Castracane V. D., Leptin in pregnancy [In Process Citation], Biol. Reprod., 63:1219, 2000. [DOI] [PubMed] [Google Scholar]
  • 43. Marti A., Berraondo B., Martinez J. A., Leptin: physiological actions, J. Physiol. Biochem., 55:43, 1999. [PubMed] [Google Scholar]
  • 44. Green H., Kehinde O., Formation of normally differentiated subcutaneous fat pads by an established preadipose cell line, J. Cell Physiol., 101:169, 1979. [DOI] [PubMed] [Google Scholar]
  • 45. Bouloumie A., Drexler H. C., Lafontan M., Busse R., Leptin, the product of Ob gene, promotes angiogenesis, Circ. Res., 83:1059, 1998. [DOI] [PubMed] [Google Scholar]
  • 46. Sierra‐Honigmann M. R., Nath A. K., Murakami C., Garcia‐Cardena G., Papapetropoulos A., Sessa W. C., Madge L. A., Schechner J. S., Schwabb M. B., Polverini P. J., Flores‐Riveros J. R., Biological action of leptin as an angiogenic factor [see comments], Science, 281:1683, 1998. [DOI] [PubMed] [Google Scholar]
  • 47. Uckaya G., Ozata M., Bayraktar Z., Erten V., Bingol N., Ozdemir I. C., Is leptin associated with diabetic retinopathy?, Diabetes Care, 23:371, 2000. [DOI] [PubMed] [Google Scholar]
  • 48. Bertolini F., Paolucci M., Peccatori F., Cinieri S., Agazzi A., Ferrucci P. F., Cocorocchio E., Goldhirsch A., Martinelli G., Angiogenic growth factors and endostatin in non‐Hodgkin's lymphoma [see comments], Br. J. Haematol., 106:504, 1999. [DOI] [PubMed] [Google Scholar]
  • 49. Tessitore L., Vizio B., Jenkins O., De Stefano I., Ritossa C., Argiles J. M., Benedetto C., Mussa A., Leptin expression in colorectal and breast cancer patients, Int. J. Mol. Med, 5:421, 2000. [DOI] [PubMed] [Google Scholar]
  • 50. Simons J. P., Schols A. M., Campfield L. A., Wouters E. F., Saris W. H., Plasma concentration of total leptin and human lung‐cancer associated cachexia, Clin. Sci. (Colch.) 93:273, 1997. [DOI] [PubMed] [Google Scholar]
  • 51. Zhang N., Deuel T. F., Pleiotrophin and midkine, a family of mitogenic and angiogenic heparin‐binding growth and differentiation factors, Curr. Opin. Hematol., 6:44, 1999. [DOI] [PubMed] [Google Scholar]
  • 52. Choudhuri R., Zhang H. T., Donnini S., Ziche M., Bicknell R., An angiogenic role for the neurokines midkine and pleiotrophin in tumorigenesis, Cancer Res., 57:1814, 1997. [PubMed] [Google Scholar]
  • 53. O'Brien T., Cranston D., Fuggle S., Bicknell R., Harris AL., The angiogenic factor midkine is expressed in bladder cancer, and overexpression correlates with a poor outcome in patients with invasive cancers, Cancer Res., 56:2515, 1996. [PubMed] [Google Scholar]
  • 54. Kato M., Maeta H., Kato S., Shinozawa T., Terada T., Immunohistochemical and in situ hybridization analyses of midkine expressionin thyroid papillary carcinoma [In Process Citation], Mod. Pathol., 13:1060, 2000. [DOI] [PubMed] [Google Scholar]
  • 55. Kato M., Shinozawa T., Kato S., Awaya A., Terada T., Increased midkine expression in hepatocellular carcinoma, Arch. Pathol. Lab. Med., 124:848, 2000. [DOI] [PubMed] [Google Scholar]
  • 56. Kato H., Watanabe K., Murari M., Isogai C., Kinoshita T., Nagai H., Ohashi H., Nagasaka T., Kadomatsu K., Muramatsu H., Muramatsu T., Saito H, Mori N., Murate T., Midkine expression in Reed‐Sternberg cells of Hodgkin's disease, Leuk. Lymphoma, 37:415, 2000. [DOI] [PubMed] [Google Scholar]
  • 57. Ikematsu S., Yano A., Aridome K., Kikuchi M., Kumai H., Nagano H., Okamoto K., Oda M., Sakuma S., Aikou T., Muramatsu H., Kadomatsu K., Muramatsu T., Serum midkine levels are increased in patients with various types of carcinomas, Br. J. Cancer, 83:701, 2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 58. Garver R. I. Jr., Radford D. M., Donis‐Keller H., Wick M. R., Milner P. G., Midkine and pleiotrophin expression in normal and malignant breast tissue, Cancer, 74:1584, 1994. [DOI] [PubMed] [Google Scholar]
  • 59. Zou Z., Anisowicz A., Hendrix M. J., Thor A., Neveu M., Sheng S., Rafidi K., Seftor E., Sager R., Maspin, a serpin with tumor‐suppressing activity in human mammary epithelial cells [see comments], Science, 263:526, 1994. [DOI] [PubMed] [Google Scholar]
  • 60. Umekita Y., Hiipakka R. A., Liao S., Rat and human maspins: structures, metastatic suppressor activity and mutation in prostate cancer cells, Cancer Lett., 113:87, 1997. [DOI] [PubMed] [Google Scholar]
  • 61. Sager R., Sheng S., Pemberton P., Hendrix M. J., Maspin. A tumor suppressing serpin, Adv. Exp. Med. Biol., 425:77, 1997. [PubMed] [Google Scholar]
  • 62. Sheng S., Carey J., Seftor E. A., Dias L., Hendrix M. J., Sager R., Maspin acts at the cell membrane to inhibit invasion and motility of mammary and prostatic cancer cells, Proc. Natl. Acad. Sci. U S A, 93:11669, 1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 63. Zhang M., Sheng S., Maass N., Sager R., mMaspin: the mouse homolog of a human tumor suppressor gene inhibits mammary tumor invasion and motility, Mol. Med. 3:49, 1997. [PMC free article] [PubMed] [Google Scholar]
  • 64. Zhang M., Volpert O., Shi Y. H., Bouck N., Maspin is an angiogenesis inhibitor, Nat. Med. 6:196, 2000. [DOI] [PubMed] [Google Scholar]
  • 65. Xia W., Lau Y. K., Hu M. C., Li L., Johnston D. A., Sheng S., El‐Naggar A., Hung MC., High tumoral maspin expression is associated with improved survival of patients with oral squamous cell carcinoma, Oncogene, 19:2398, 2000. [DOI] [PubMed] [Google Scholar]
  • 66. Stefansson S., Petitclerc E., Wong M. K., McMahon G. A., Brooks P. C., Lawrence D. A., Inhibition of angiogenesis in vivo by plasminogen activator inhibitor‐1, J. Biol. Chem., in press. [DOI] [PubMed]
  • 67. O'Reilly M. S., Pirie‐Shepherd S., Lane W. S., Folkman J., Antiangiogenic activity of the cleaved conformation of the serpin antithrombin, Science, 285:1926, 1999. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Cellular and Molecular Medicine are provided here courtesy of Blackwell Publishing

RESOURCES