Review Article | Published:

Angiogenesis in cancer and other diseases

Nature volume 407, pages 249257 (14 September 2000) | Download Citation

Subjects

Abstract

Pathological angiogenesis is a hallmark of cancer and various ischaemic and inflammatory diseases. Concentrated efforts in this area of research are leading to the discovery of a growing number of pro- and anti-angiogenic molecules, some of which are already in clinical trials. The complex interactions among these molecules and how they affect vascular structure and function in different environments are now beginning to be elucidated. This integrated understanding is leading to the development of a number of exciting and bold approaches to treat cancer and other diseases. But owing to several unanswered questions, caution is needed.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    The growth of malignant disease in man and the lower animals with special reference to the vascular system. Lancet 2, 1236–1240 (1907).

  2. 2.

    , & Vascularization of the Brown-Pearce rabbit epithelioma transplant as seen in the transparent ear chamber. Am. J. Radiol. 42, 891–899 ( 1939).

  3. 3.

    & Vascular reactions of normal and malignant tissues in vivo. I. Vascular reactions of mice to wounds and to normal and neoplastic transplants. J. Natl Cancer Inst. USA 6, 73–85 (1945 ).

  4. 4.

    & Tumor angiogenesis: transfilter diffusion studies in the hamster by the transparant chamber technique. J. Natl Cancer Inst. 41, 111–124 (1968).

  5. 5.

    & Choriocarcinoma: transfilter stimulation of vasoproliferation in the hamster cheek pouch studied by light and electron microscopy. J. Natl Cancer Inst. 41, 1329 –1341 (1968).

  6. 6.

    in Cancer Medicine (eds Holland, J. F. et al.) 132– 152 (Decker, Ontario, Canada, 2000).

  7. 7.

    Angiogenesis and oncogenesis. J. Natl Cancer Inst. 61, 639–643 (1978).

  8. 8.

    & The hallmarks of cancer. Cell 100, 57–70 ( 2000).

  9. 9.

    , & How tumors become angiogenic. Adv. Cancer Res. 69, 135–174 ( 1996).

  10. 10.

    Tumor angiogenesis: past, present and the near future. Carcinogenesis 21, 505–515 ( 2000).

  11. 11.

    Controlling the cellular brakes. Nature 401, 657–658 (1999).

  12. 12.

    et al. Tumor induction of VEGF promoter activity in stromal cells . Cell 94, 715–725 (1998).

  13. 13.

    , , , & Local imbalance of proangiogenic and antiangiogenic factors: a potential mechanism of focal necrosis and dormancy in tumors. Cancer Res. 60, 1442– 1448 (2000).

  14. 14.

    , & Intussusceptive microvascular growth in a human colon adenocarcinoma xenograft: a novel mechanism of tumor angiogenesis. Microvasc. Res. 51, 260–272 (1996).

  15. 15.

    , & Stem cell therapy and gene transfer for regeneration . Gene Ther. 7, 451–457 (2000).

  16. 16.

    Circulating endothelial precursors: mystery, reality, and promise. J. Clin. Invest. 105, 17–19 (2000).

  17. 17.

    Mechanisms of angiogenesis and arteriogenesis. Nature Med. 6, 389–395 (2000).

  18. 18.

    et al. Abnormal blood vessel development and lethality in embryos lacking a single vascular endothelial growth factor allele. Nature 380, 435–439 ( 1996).

  19. 19.

    & Clinical applications of angiogenic growth factors and their inhibitors. Nature Med. 5, 1359–1364 (1999).

  20. 20.

    , , , & Selective ablation of immature blood vessels in established human tumors follows vascular endothelial growth factor withdrawal. J. Clin. Invest. 103, 159–165 (1999).

  21. 21.

    Determinants of tumor blood flow: a review. Cancer Res. 48, 2641–2658 (1988).

  22. 22.

    et al. Abundance of neoplastic cells in vessel walls of human tumor xenografts. Proc. Am. Assoc. Cancer Res. (in the press).

  23. 23.

    & Fractals and cancer. Cancer Res. 60, 3683–3688 (2000).

  24. 24.

    , , & Interstitial pH and pO2 gradients in solid tumors in vivo: high-resolution measurements reveal a lack of correlation. Nature Med. 3, 177 –182 (1997).

  25. 25.

    Hypoxic stress proteins: survival of the fittest. Semin. Radiat. Oncol. 6, 46–58 ( 1996).

  26. 26.

    et al. Heterogeneity of angiogenesis and blood vessel maturation in human tumors: implications for antiangiogenic tumor therapies. Cancer Res. 60, 1388–1393 (2000).

  27. 27.

    et al. Regulation of transport pathways in tumor vessels: role of tumor type and microenvironment. Proc. Natl Acad. Sci. USA 95, 4607–4612 (1998).

  28. 28.

    et al. Openings between defective endothelial cells explain tumor vessel leakiness. Am. J. Pathol. 156, 1363 –1380 (2000).

  29. 29.

    , , , & Vascular permeability factor/vascular endothelial growth factor and the significance of microvascular hyperpermeabiltiy in angiogenesis . Curr. Top. Microbiol. Immunol. 237, 97 –132 (1999).

  30. 30.

    et al. Endothelial cell death, angiogenesis, and microvascular function after castration in an androgen-dependent tumor: role of vascular endothelial growth factor. Proc. Natl Acad. Sci. USA 95, 10820–10825 (1998).

  31. 31.

    , , , & Effect of host microenvironment on the microcirculation of human colon adenocarcinoma. Am. J. Pathol. 151, 679–688 (1997).

  32. 32.

    Modulation of the organ microenvironment for treatment of cancer metastasis . J. Natl Cancer Inst. 87, 1588– 1592 (1995).

  33. 33.

    & Leaky vessels? Call Ang1!. Nature Med. 6, 131–132 ( 2000).

  34. 34.

    et al. Leukocyte-endothelial adhesion and angiogenesis in tumors . Cancer Metastasis Rev. 15, 195– 204 (1996).

  35. 35.

    & The role of alphav integrins during angiogenesis: insights into potential mechanisms of action and clinical development. J. Clin. Invest. 103 , 1227–1230 (1999).

  36. 36.

    et al. Tumor infarction in mice by antibody-directed targeting of tissue factor to tumor vasculature. Science 275, 547–550 (1997).

  37. 37.

    , & Cancer treatment by targeted drug delivery to tumor vasculature in a mouse model. Science 279, 377–380 (1998).

  38. 38.

    , , , & Absence of functional lymphatics within a murine sarcoma: a molecular and functional evaluation. Cancer Res. 60, 4324–4327 (2000).

  39. 39.

    , , , & Solid stress inhibits the growth of multicellular tumor spheroids. Nature Biotechnol. 15, 778–783 (1997).

  40. 40.

    et al. Hyperplasia of lymphatic vessels in VEGF-C transgenic mice . Science 276, 1423–1425 (1997).

  41. 41.

    Barriers to drug delivery in solid tumors. Sci. Am. 271, 58–65 (1994).

  42. 42.

    et al. Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma. Cell 79, 315–328 (1994).

  43. 43.

    et al. Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell 88, 277–285 (1997).

  44. 44.

    et al. Tumor-host interactions in the gallbladder suppress distal angiogenesis and tumor growth: involvement of transforming growth factor beta1 . Nature Med. 5, 1203–1208 (1999).

  45. 45.

    , , & Irradiation of a primary tumor, unlike surgical removal, enhances angiogenesis suppression at a distal site: potential role of host-tumor interaction. Cancer Res. 60, 2128–2131 (2000).

  46. 46.

    et al. Spectrum of tumor angiogenesis in the bone marrow of children with acute lymphoblastic leukemia. Am. J. Pathol. 150 , 815–821 (1997).

  47. 47.

    , , & Expression of vascular endothelial growth factor and its receptors in hematopoietic malignancies. Cancer Res. 59, 728– 733 (1999).

  48. 48.

    , , & Molecular basis of vascular anomalies. Trends Cardiovasc. Med. 8, 281–292 ( 1998).

  49. 49.

    et al. The angiogenesis induced by HIV-1 tat protein is mediated by the Flk-1/KDR receptor on vascular endothelial cells. Nature Med. 2, 1371–1375 ( 1996).

  50. 50.

    et al. Transformation of primary human endothelial cells by Kaposi's sarcoma-associated herpesvirus. Nature 394, 588–592 (1998).

  51. 51.

    & Diabetic neuropathy . Med. Clin. North Am. 82, 909– 929 (1998).

  52. 52.

    Hypoxia-inducible factor 1: master regulator of O2 homeostasis . Curr. Opin. Genet. Dev. 8, 588– 594 (1998).

  53. 53.

    et al. Vascular endothelial growth factor acts as a survival factor for newly formed retinal vessels and has implications for retinopathy of prematurity . Nature Med. 1, 1024–1028 (1995).

  54. 54.

    Pulmonary hypertension: pathophysiology as a basis for clinical decision making . J. Heart Lung Transpl. 18, 1041– 1053 (1999).

  55. 55.

    , , & Involvement of platelets in tumour angiogenesis? Lancet 352, 1775–1777 (1998).

  56. 56.

    , & Tumor stroma. Anticancer Res. 19, 4809–4822 (1999).

  57. 57.

    & Molecular mechanisms of coronary collateral vessel growth. Circ. Res. 79, 911–919 (1996).

  58. 58.

    et al. Inflammatory mast cells up-regulate angiogenesis during squamous epithelial carcinogenesis. Genes Dev. 13, 1382–1397 (1999).

  59. 59.

    et al. Inhibition of plasminogen activators or matrix metalloproteinases prevents cardiac rupture but impairs therapeutic angiogenesis and causes cardiac failure. Nature Med. 5, 1135– 1142 (1999).

  60. 60.

    & Development and disease in proteinase-deficient mice: role of the plasminogen, matrix metalloproteinase and coagulation system . Thromb. Res. 91, 255– 285 (1998).

  61. 61.

    & The pathophysiology of the collateral circulation (arteriogenesis). J. Pathol. 190, 338–342 (2000).

  62. 62.

    et al. Angiogenic activity of adipose tissue. Biochem. Biophys. Res. Commun. 153, 347–352 (1988).

  63. 63.

    et al. Biological action of leptin as an angiogenic factor. Science 281, 1683–1686 ( 1998).

  64. 64.

    & Angiogenesis and vasculogenesis as therapeutic strategies for postnatal neovascularization. J. Clin. Invest. 103, 1231–1236 (1999).

  65. 65.

    et al. Impaired myocardial angiogenesis and ischemic cardiomyopathy in mice lacking the vascular endothelial growth factor isoforms VEGF164 and VEGF188. Nature Med. 5, 495– 502 (1999).

  66. 66.

    et al. PR39, a peptide regulator of angiogenesis. Nature Med. 6, 49–55 (2000 ).

  67. 67.

    et al. Role of HIF-1α in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis. Nature 394, 485 –490 (1998).

  68. 68.

    & Chemotherapeutic drugs—more really is not better. Nature Med. 6, 500 –502 (2000).

  69. 69.

    , , , & Genetic heterogeneity of angiogenesis in mice. FASEB J. 14, 871– 876 (2000).

  70. 70.

    et al. Targeted deficiency or cytosolic truncation of the VE-cadherin gene in mice impairs VEGF-mediated endothelial survival and angiogenesis. Cell 98, 147–157 ( 1999).

  71. 71.

    et al. Absence of host plasminogen activator inhibitor 1 prevents cancer invasion and vascularization. Nature Med. 4, 923–928 (1998).

  72. 72.

    & Transgenic mouse models in angiogenesis and cardiovascular disease. J. Pathol. 190, 387–405 (2000).

  73. 73.

    , , & Quantitative angiogenesis assays: progress and problems. Nature Med. 3, 1203–1208 ( 1997).

  74. 74.

    et al. VEGF modulation by targeting HIF-1alpha/HRE/VEGF cascade differentially regulates vascular response and growth rate in tumors. Cancer Res. (in the press).

  75. 75.

    et al. Angiogenesis, microvascular architecture, microhemodynamics, and interstitial fluid pressure during early growth of human adenocarcinoma LS174T in SCID mice. Cancer Res. 52, 6553 –6560 (1992).

Download references

Acknowledgements

We acknowledge the critical input of C. Mouta Carreira, B. Fenton, D. Fukumura, J. Samson, A. Kadambi, B. Stoll and E. diTomaso in manuscript preparation and L. L. Munn, M. Leunig and A. Vandenhoeck in figure preparation. This work was supported by grants from the NIH, NSF, DOD, ACS, the National Foundation for Cancer Research and the Whitaker Foundation (R.K.J.), and from the VIB, FWO, Biomed and the VLK (P.C.). Owing to space limitations we have cited review articles instead of original references; relevant material that could not be included in this review is available at http://steele.mgh.harvard.edu.

Author information

Affiliations

  1. *The Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology, KU Leuven, Leuven, B-3000, Belgium (e-mail: peter.carmeliet@med.kuleuven.ac.be)

    • Peter Carmeliet
  2. †Steele Laboratory for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114 , USA (e-mail: jain@steele.mgh.harvard.edu)

    • Rakesh K. Jain

Authors

  1. Search for Peter Carmeliet in:

  2. Search for Rakesh K. Jain in:

About this article

Publication history

Published

DOI

https://doi.org/10.1038/35025220

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Newsletter Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing