Angiogenesis and Oxygen Transport in Solid Tumors

  • Zishan A. Haroon
  • Kevin G. Peters
  • Charles S. Greenberg
  • Mark W. Dewhirst
Part of the Cancer Drug Discovery and Development book series (CDD&D)


Angiogenesis, the formation of new vessels from existing microvasculature, is a tremendously complex and intricate process, essential for embryogenesis and development of multicellular organisms (1), but it occurs only rarely in adult tissues in a tightly controlled manner during normal wound healing and the female reproductive cycle (corpus luteum, placenta, and uterus) (2). When these tight controls are breached, the result is unchecked angiogenesis, which has been implicated in the development and progression of a variety of diseases (Table 1). The prevalence of pathologic angiogenesis in human diseases, and the significant mortality associated with these disorders, underscore the importance and emergence of antiangiogenesis therapy as a major clinical tool. In the case of solid malignancies, the generation of proangiogenic substances is in part caused by the pathologic microenvironment that develops in response to uncoordinated vascular production.


Nitric Oxide Vascular Endothelial Growth Factor Oxygen Transport Oxygen Consumption Rate Chronic Hypoxia 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Hamilton, W. J., Boyd, J. D., and Mossman, H. W. (1962) Human Embryology, William and Wilkins, Baltimore.Google Scholar
  2. 2.
    Folkman, J. and Shing, Y. (1992) Angiogenesis. J. Biol. Chem. 267, 10,931–10,934.Google Scholar
  3. 3.
    Blood, C. A. and Zetter, B. R. (1990) Tumor interactions with the vasculature: angiogenesis and tumor metastasis. Biochim. Biophys. Acta 1032, 89–118.Google Scholar
  4. 4.
    Clark, R. A. F. (1996) Wound repair: overview and general considerations, in Molecular and Cellular Biology of Wound Repair, 2nd ed. (Clark, R. A. F., ed.), Plenum, New York, pp. 1–50.Google Scholar
  5. 5.
    Ausprunk, D. H. and Folkman, J. (1977) Migration and proliferation of endothelial cells in preformed and newly formed blood vessels during tumor angiogenesis. Microvasc. Res. 14, 53–65.PubMedCrossRefGoogle Scholar
  6. 6.
    Mustohen, T. and Alitalo, K. (1995) Endothelial receptor tyrosine kinases involved in angiogenesis. J. Cell Biol. 129, 895–898.CrossRefGoogle Scholar
  7. 7.
    Brown, L. F., Detmar, M., Claffey, K, Nagy, J. A., Feng, D., Dvorak, A. M., and Dvorak, H. F. (1997) Vascular permeability factor/vascular endothelial growth factor: a multifunctional angiogenic cytokine. EXS. Regul. Angiogenesis 79, 233–269.Google Scholar
  8. 8.
    Dvorak, H. F., Brown, L. F., Detmar, M., and Dvorak, A. M. (1995) Vascular permeability factor/ vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis. Am. J Pathol. 146, 1029–1039.Google Scholar
  9. 9.
    Folkman, J. (1997) Angiogenesis and angiogenesis inhibition: an overview. EXS Regul. Angiogenesis 79, 1–7.Google Scholar
  10. 10.
    Pepper, M. S., Montesano, R., Mandriota, S. J., Orci, L., and Vassalli, J-D (1996) Angiogenesis: a paradigm for balanced extracellular proteolysis during cell migration and morphogenesis. Enzyme Protein 49, 138–162.PubMedGoogle Scholar
  11. 11.
    Flaumenhaft, R. and Rifkin, D. B. (1992) Extracellular regulation of growth factor action. Mol. Biol. Cell. 3, 1057–1065.Google Scholar
  12. 12.
    O’Reilly, M. S., Holmgren, L., Shing, Y., Chen, C., Rosenthal, R. A., Moses, M., et al. (1994) Angistatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma. Cell 79, 315–328.PubMedCrossRefGoogle Scholar
  13. 13.
    Mignatti, P. and Rifkin, D. B. (1996) Plasminogen activators and matrix metalloproteinases in angiogenesis. Enzyme Protein 49, 117–137.PubMedGoogle Scholar
  14. 14.
    Hu, D. E., Hori, Y., and Fan, T. P. (1993) Interleukin-8 stimulates angiogenesis in rats. Inflammation 17(2), 135–143.PubMedCrossRefGoogle Scholar
  15. 15.
    Adams, D. H. and Lloyd, A. R. (1997) Chemokines: leucocyte recruitment and activation cytokines. Lancet 349, 490–495.PubMedCrossRefGoogle Scholar
  16. 16.
    Polverini, P. J. (1997) Role of macrophages in angiogenesis-dependent disease. EXS Regul. Angiogenesis 79, 11–28.Google Scholar
  17. 17.
    Meininger, C. J. (1995) Mast cells and tumor associated angiogenesis. Chem. Immunol. 62, 239–257.Google Scholar
  18. 18.
    Battegay, E. J. (1995) Angiogenesis: mechanistic insights, neovascular diseases, and therapeutic prospects. J. Mol. Med. 73, 333–346.Google Scholar
  19. 19.
    Brooks, P. C. (1996) Role of integrins in angiogenesis. Eur. J. Cancer 32A, 2423–2429.Google Scholar
  20. 20.
    Varner, J. A. (1997) The role of vascular cell integrins avββ3 and avβ5 in angiogenesis. EXS Regul. Angiogenesis 79, 361–390.Google Scholar
  21. 21.
    Maisonpierre, P. C., Suri, C., Jones, P. F., Bartunkova, S., Wiegand, S., Radziejewski, C., et al. (1997) Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. Science 277, 55–60.PubMedCrossRefGoogle Scholar
  22. 22.
    Sato, T. N., Tazawa, Y., Deutsch, U., Wolburg, H., Risau, W., and Qin, Y. (1995) Distinct roles of the receptor tyrosine kinases Tie-1 and Tie-2 in blood vessel formation. Nature 376, 70–74.PubMedCrossRefGoogle Scholar
  23. 23.
    Wong, A. L., Haroon, Z. A., Werner, S., Dewhirst, M. W., Greenberg, C. S., and Peters, K. G. (1997) Expression and phosphorylation of Tie-2 in adult rat tissue suggest a dual role in angiogenesis and vascular maintenance. Circ. Res. 81, 567–574.Google Scholar
  24. 24.
    Haddow, A. (1972) Molecular repair, wound healing, and carcinogenesis: tumor production a possible overhealing? Adv. Cancer Res. 16, 181–234.CrossRefGoogle Scholar
  25. 25.
    Dvorak, H. F. (1986) Tumors: wounds that do not heal. New Eng. J. Med. 315(26), 1650–1659.CrossRefGoogle Scholar
  26. 26.
    van Hinsbergh, V. W. M., Koolwijk, P., and Hanemaaijer, R. (1997) Role of fibrin and plasminogen activators in repair-associated angiogenesis: in vitro studies with human endothelial cells. EXS Regul. Angiogenesis 79, 391–411.Google Scholar
  27. 27.
    Enholm, B., Paavonen, K., Ristimaki, A., Kumar, V., Gunji, Y., Klefstrom, J., et al. (1997) Comparison of VEGF, VEGF-B, VEGF-C and Angiogenesis-1 mRNA regulation by serum, growth factors, oncoproteins and hypoxia. Oncogene 14, 2475–2483.PubMedCrossRefGoogle Scholar
  28. 28.
    Kuwabara, K., Ogawa, S., Matsumoto, M., Koga, S., Clauss, M., Pinsky, D., et al. (1995) Hypoxiamediated induction of acidic/basic fibroblast growth factor and platelet-derived growth factor in mononuclear phagocytes stimulates growth of hypoxic endothelial cells. Proc. Natl. Acad. Sci. USA 922, 4606–4610.Google Scholar
  29. 29.
    Waltenberger J., Mayr, U., Pentz, S., and Hombach, V. (1996) Functional upregulation of the vascular endothelial growth factor receptor KDR by hypoxia. Circulation 94, 1647–1654.PubMedCrossRefGoogle Scholar
  30. 30.
    Detmar, M., Brown, L., Berse, B., Jackman, R., Elicker, B., Dvorak, H., and Claffey, K. (1997) Hypoxia regulates the expression of VPF/VEGF and its receptors in human skin. J. Inves. Dermatol. 108,263–268.Google Scholar
  31. 31.
    Karakurum, M., Shreeniwas, R., Chen, J., Pinsky, D., Yan, S.-D., Anderson, M., et al. (1994) Hypoxic induction of interleukin-8 gene expression in human endothelial cells. J. Clin. Invest. 93, 1564–1570.PubMedCrossRefGoogle Scholar
  32. 32.
    Gleadle, J., Ebert, B., Firth, J., and Ratcliffe, P. (1995) Regulation of angiogenic growth factor expression by hypoxia, transition metals, and chelating agents. Am. J. Physiol. 268, C 1362–C 1368.Google Scholar
  33. 33.
    Patel, B., Khaliq, A., Jarvis-Evans, J., Mcleod, D., Mackness, M., and Boulton, M. (1994) Oxygen regulation of TGF β1 mRNA in human hepatoma (HEP G2) cells. Biochem. Mol. Biol. Int. 34, 639–644.PubMedGoogle Scholar
  34. 34.
    Sampson, L. and Chaplin, D. (1996) The influence of oxygen and carbon dioxide tension on the production of TNF a by activated macrophages. Br. J. Cancer 74(Suppl. XXVII), S133–S135.Google Scholar
  35. 35.
    Minchenko, A., Salceda, S., Bauer, T., and Caro, J. (1994) Hypoxia regulatory elements of the human VEGF gene. Cell Mol. Biol. Res. 40, 35–39.Google Scholar
  36. 36.
    Brizel, D. M., Scully, S. P., Harrelson, J. M., Layfield, L., Bean, J., Prosnitz, L., and Dewhirst, M. (1996) Tumor oxygenation predicts for the likelihood of distant metastases in human soft tissue sarcoma. Cancer Res. 56, 941–943.PubMedGoogle Scholar
  37. 37.
    Hockel, M., Schlenger, K., Aral, B., Mitze, M., Schaffer, U., and Vaupel, P. (1996) Association between tumor hypoxia and malignant progression in advanced cancer of the uterine cervix. Cancer Res. 56, 4509–4515.PubMedGoogle Scholar
  38. 38.
    Weidner, N., Semple, J. P., Welch, W. R., and Folkman, J. (1991) Tumor angiogenesis and metastasiscorelation in invasive breast carcinoma. N. Engl. J. Med. 324, 1–8.Google Scholar
  39. 39.
    Rak, J., Filmus, J., Finkenzeller, G., Grugel, S., Marme, D., and Kerbel, R. S. (1995) Oncogenes as inducers of tumor angiogenesis. Cancer Metastasis Rev. 14, 263–277.PubMedCrossRefGoogle Scholar
  40. 40.
    Relf, M., LeJeune, S., Scott, P., Fox, S., Smith, K., Leek, R., et al. (1997) Expression of the angiogenic factors VEGF, acidic and basic FGF, TGF β-1, platelet-derived endothelial cell growth factor, placenta growth factor, and pleiotrophin in human primary breast cancer and its relation to angiogenesis. Cancer Res. 57, 963–969.Google Scholar
  41. 41.
    Thomlinson, R. H. and Gray, L. H. (1955) Histological structure of some human lung cancers and the possible implications for radiotherapy.Br. J. Cancer 9, 539–549.PubMedCrossRefGoogle Scholar
  42. 42.
    Overgaard, J. and Horsman, M. R. (1996) Modification of hypoxia-induced radioresistance in tumors by the use of oxygen and sensitizers. Semin. Radiat. Oncol. 6, 10–21.PubMedCrossRefGoogle Scholar
  43. 43.
    Dewhirst, M. W., Ong, E. T., Klitzman, B., Secomb, T., Vinuya, R., Dodge, R., Brizel, D., and Gross, J. (1992) Perivascular oxygen tensions in a transplantable mammary tumor growing in a dorsal flap window chamber. Radiat. Res. 130, 171–182.Google Scholar
  44. 44.
    Helmlinger, G., Yuan, F., Dellian, M., Jain, R. K. (1997) Interstitial pH and P02 gradients in solid tumors in vivo: high-resolution measurements reveal a lack of correlation. Nature Med. 3, 177–182.PubMedCrossRefGoogle Scholar
  45. 45.
    Dewhirst, M. W., Ong, E. T., Rosner, G. L., Rhemus, S., Shan, S., Braun, R., Brizel, D., and Secomb, T. (1996) Arteriolar oxygenation in tumour and subcutaneous arterioles: effects of inspired air oxygen content. Br. J. Cancer 74(Suppl. XXVII), S241–S246.Google Scholar
  46. 46.
    Intaglietta, M., Johnson, P. C., and Winslow, R. M. (1996) Microvascular and tissue oxygen distribution. Cardiovasc. Res. 32, 632–643.PubMedGoogle Scholar
  47. 47.
    Vaupel, P., Kallinowski, F., and Okunieff, P. (1989) Blood flow, oxygen, nutrient supply and metabolic microenvironment of human tumors: a review. Cancer Res. 49, 6449–6465.PubMedGoogle Scholar
  48. 48.
    Secomb, T. W., Hsu, R., Braun, R. D., Ross, J. R., Gross, J., and Dewhirst, M. (1997) Theoretical simulation of oxygen transport to tumors by three-dimensional networks of microvessels. Adv. Exp. Biol. Med., in press.Google Scholar
  49. 49.
    Dewhirst, M., Ong, E., Smith, B., Evans, S., Secomb, T., and Wilson, D. (1996) Longitudinal gradients of vascular PO2 in R3230AC tumor microvessels in dorsal flap window chambers, in Sixth World CongressforMicrocirculation (Messmer, K. and Kubler, W., eds.), Monduzzi Editore S. p. A., Bologna, Italy, pp. 343–346.Google Scholar
  50. 50.
    Kavanagh, B. D., Coffey, B. E., Needham, D., Hochmuth, R., and Dewhirst, M. (1993) The effect of flunarizine on the viscosity of human and rat erythrocyte suspensions in conditions of extreme hypoxia and lactic acidosis. Br. J. Cancer 67, 734–741.PubMedCrossRefGoogle Scholar
  51. 51.
    Dewhirst, M. W., Ong, E. T., Madwed, D., Klitzman, B., Secomb, T., Brizel, D., et al. (1992) Effects of the calcium channel blocker flunarizine on the hemodynamics and oxygenation of tumor microvasculature. Radiat. Res. 132, 61–68.PubMedCrossRefGoogle Scholar
  52. 52.
    Dewhirst, M. W., Secomb, T. W., Ong, E. T., Hsu, R., and Gross, J. (1994) Determination of local oxygen consumption rates in tumors. Cancer Res. 54, 3333–3336.PubMedGoogle Scholar
  53. 53.
    Secomb, T. W., Hsu, R., Dewhirst, M. W., Klitzman, B., and Gross, J. F. (1993) Analysis of oxygen transport to tumor tissue by microvascular networks. Int. J. Radiat. Oncol. Biol. Phys. 25, 481–489.PubMedCrossRefGoogle Scholar
  54. 54.
    Dewhirst, M. W., Kimura, H., Rehmus, S. W. E., Braun, R., Papahadjopoulos, D., Hong, K., and Secomb, T. (1996) Microvascular studies on the origins of perfusion-limited hypoxia. Br. J. Cancer 74, S247–S251.Google Scholar
  55. 55.
    Kallinowski, F., Schlenger, K. H., Runkel, S., Kloes, M., Stohrer, M., Okunieff, P., and Vaupel, P. (1989) Blood flow, metabolism, cellular microenvironment, and growth rate ofhuman tumor xenografts.Cancer Res. 49, 3759–3764.PubMedGoogle Scholar
  56. 56.
    Secomb, T. W., Hsu, R., Ong, E. T., Gross, J., and Dewhirst, M. (1995) Analysis of the effects of oxygen supply and demand on hypoxic fraction in tumors. Acta Oncol. 34, 313–316.Google Scholar
  57. 57.
    Kimura, H., Braun, R. D., Ong, E. T., Hsu, R., Secomb, T., Papahadjopoulos, D., Hong, K., and Dewhirst, M. (1996) Fluctuations in red cell flux in tumor microvessels can lead to transient hypoxia and reoxygenation in tumor parenchyma. Cancer Res. 56, 5522–5528.PubMedGoogle Scholar
  58. 58.
    Chaplin, D. J., Durand, R. E., and Olive, P. (1986) Acute hypoxia in tumors: implications for modifiers of radiation effects. Int. J. Radiat. Oncol. Biol. Phys. 12, 1279–1282.PubMedCrossRefGoogle Scholar
  59. 59.
    Trotter, M. J., Olive, P. L., and Chaplin, D. J. (1990) Effect ofvascular marker Hoechst 33342 on tumour perfusion and cardiovascular function in the mouse. Br. J. Cancer 62, 903–908.PubMedCrossRefGoogle Scholar
  60. 60.
    Chaplin, D. J. and Hill, S. A. (1995) Temporal heterogeneity in microregional erythrocyte flux in experimental solid tumors. Br. J. Cancer 71, 1210–1213.PubMedCrossRefGoogle Scholar
  61. 61.
    Hill, S. A., Pigott, K. H., Saunders, M. I., Powell, M., Arnold, S., Obeid, A., et al. (1996) Microregional blood flow in murine and human tumours assessed using laser Doppler microprobes. Br. J. Cancer 74, S260–S263.Google Scholar
  62. 62.
    Li, X., Brown, S. L., and Hill, R. P. (1992) Factors influencing the thermosensitivity of two rodent tumors. Radiat. Res. 130, 211–219.PubMedCrossRefGoogle Scholar
  63. 63.
    Dewhirst, M. W., Braun, R. D., and Lanzen, J. L. (1998) Temporal changes in PO2 of R3230 Ac tumors, in Fischer-344 rats. Int. J. Radiat. Oncol. Biol. Phys., submitted.Google Scholar
  64. 64.
    Graeber, T. G., Osmanian, C., and Jacks, T. (1996) Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumours [see comments]. Nature 379, 88–91.PubMedCrossRefGoogle Scholar
  65. 65.
    Welbourn, C. R. B., Goldman, G., Paterson, I. S., Valeri, C., Shepro, D., and Hechtman, H. (1991) Pathophysiology of ischemia reperfusion injury-central role of the neutrophil. Br. J. Surg. 78, 651.PubMedCrossRefGoogle Scholar
  66. 66.
    Reynolds, T. Y., Rockwell, S., and Glazer, P. M.(1996) Genetic instability induced by the tumor microenvironment. Cancer Res. 56, 5754–5757.PubMedGoogle Scholar
  67. 67.
    Patan, S., Munn, L. L., and Jain, R. K. (1996) Intussusceptive microvascular growth in a human colon adneocarcinoma xenograft: a novel mechanism of tumor angiogenesis. Microvasc. Res. 51, 260–272.PubMedCrossRefGoogle Scholar
  68. 68.
    Kiani, M. F., Pries, A. R., Hsu, L. L., Saralius, H., and Cokelet, G. (1994) Fluctuations in microvascular blood flow parameters caused by hemodynarnic mechanisms. Am. J. Physiol. 266, H1822–H1828.Google Scholar
  69. 69.
    Schmidt-Schoenbein, G. W., Skalak, R., Usami, S., and Chien, S. (1980) Cell distribution in capillary networks. Microvasc. Res. 19, 18–44.CrossRefGoogle Scholar
  70. 70.
    Tozer, G. M. and Everett, S. A. (1997) Nitric oxide in tumour biology and cancer therapy. Part 1. Physiological aspects. Clin. Oncol. 9, 282–293.CrossRefGoogle Scholar
  71. 71.
    Wu, H. M., Huang, Q., Yuan, Y., and Granger, H. J. (1996) VEGF induces NO-dependent hyperpermeability in coronary venules. Am. J. Physiol. 271, H2735–H2739.Google Scholar
  72. 72.
    Chin, K., Kurashima, Y., Ogura, T., Tajiri, H., Yoshida, S., and Esumi, H. (1997) Induction of vascular endothelial growth factor by nitric oxide in human glioblastoma and hepatocellular carcinoma cells. Oncogene 15, 437–442.PubMedCrossRefGoogle Scholar
  73. 73.
    Ziche, M., Morbidelli, L., Masini, E., Amerini, S., Granger, H. J., Maggi, C. A., Geppetti, P., and Ledda, F. (1994) Nitric oxide mediates angiogenesis in vivo and endothelial cell growth and migration in vitro promoted by substance P. J. Clin. Invest. 94, 2036–2044.PubMedCrossRefGoogle Scholar
  74. 74.
    Morbidelli, L., Chang, C. H., Douglas, J. G., Granger, H. J., Ledda, F., and Ziche, M. (1996) Nitric oxide mediates mitogenic effect ofVEGF on coronary venular endothelium. Am. J. Physiol. 270, H411–H415.Google Scholar
  75. 75.
    Jenkins, D. C., Charles, I. G., Thomsen, L. L., Moss, D. W., Holmes, L. S., Baylis, S. A., et al. (1995) Roles of nitric oxide in tumor growth. Proc. Natl. Acad. Sci. USA 92, 4392–4396.PubMedCrossRefGoogle Scholar
  76. 76.
    Tsurumi, Y., Murohara, T., Krasinski, K., Chen, D., Witzenbichler, B., Kearney, M., Couffinhal, T., and Isner, J. M. (1997) Reciprocal relation between VEGF and NO in the regulation of endothelial integrity. Nature Med. 3, 879–886.PubMedCrossRefGoogle Scholar
  77. 77.
    Tuder, R. M., Flook, B. E., and Voelkel, N. F. (1995) Increased gene expression for VEGF and the VEGF receptors KDR/Flk and Flt in lungs exposed to acute or to chronic hypoxia. Modulation of gene expression by nitric oxide. J. Clin. Invest. 95, 1798–1807.PubMedCrossRefGoogle Scholar
  78. 78.
    Pipili-Synetos, E., Sakkoula, E., Haralabopoulos, G., Andriopoulou, P., Peristeris, P., and Maragoudakis, M. E. (1994) Evidence that nitric oxide is an endogenous antiangiogenic mediator. Br. J. Pharmacol. 111, 894–902.Google Scholar
  79. 79.
    Pipili-Synetos, E., Papageorgiou, A., Sakkoula, E., Sotiropoulou, G., Fotsis, T., Karakiulakis, G., and Maragoudakis, M. E. (1995) Inhibition of angiogenesis, tumour growth and metastasis by the NOreleasing vasodilators, isosorbide mononitrate and dinitrate. Br. J. Pharmacol. 116, 1829–1834.PubMedCrossRefGoogle Scholar
  80. 80.
    Yang, W., Ando, J., Korenaga, R., Toyo-oka, T., and Kamiya, A. (1994) Exogenous nitric oxide inhibits proliferation of cultured vascular endothelial cells. Biochem. Biophys. Res. Commun. 203, 1160–1167.Google Scholar
  81. 81.
    Lau, Y. T. and Ma, W. C. (1996) Nitric oxide inhibits migration of cultured endothelial cells. Biochem. Biophys. Res. Commun. 221, 670–674.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1999

Authors and Affiliations

  • Zishan A. Haroon
  • Kevin G. Peters
  • Charles S. Greenberg
  • Mark W. Dewhirst

There are no affiliations available

Personalised recommendations