Abstract
IT is now well established that unrestricted growth of tumours is dependent upon angiogenesis1,2. Previous studies on tumour growth, however, have not revealed when or how the transition to an angiogenic state occurs during early tumour development. The advent of transgenic mice carrying oncogenes that reproducibly elicit tumours of specific cell types3–6 is providing a new format for studying multi-step tumorigenesis7,8. In one of these models, transgenic mice expressing an oncogene in the β-cells of the pancreatic islets heritably recapitulate a progression from normality to hyperplasia to neoplasia6. We report here that angiogenic activity first appears in a subset of hyperplastic islets before the onset of tumour formation. A novel in vitro assay confirms that hyperplasia per sedoes not obligate angiogenesis. Rather, a few hyperplastic islets become angiogenic in vitro at a time when such islets are neovascularized in vivo and at a frequency that correlates closely with subsequent tumour incidence. These findings suggest that induction of angiogenesis is an important step in carcinogenesis.
Similar content being viewed by others
References
Folkman, J. New Engl. J. Med. 285, 1182–1186 (1971).
Folkman, J. & Klaysbrun, M. Science 235, 442–447 (1987).
Brinster, R. L. et al. Cell 37, 367–379 (1984).
Stewart, T. A., Pattengale, P. K. & Leder, D. Cell 38, 627–637 (1984).
Adams, J. M. et al. Nature 318, 533–538 (1985).
Hanahan, D. Nature 315, 115–122 (1985).
Hanahan, D. Oncogenes and Growth Control (eds Kahn, P. & Graf, T.) 349–363 (Springer, Heidelberg, 1986).
Hanahan, D. Ann. Rev. Genet. 22, 479–519 (1988).
Alpert, S., Hanahan, D. & Teitelman, G. Cell 53, 295–308 (1988).
Teitelman, G., Alpert, S. & Hanahan, D. Cell 52, 97–105 (1988).
Ingber, D. E., Madri, J. A. & Folkman, J. Endocrinology 119, 1768–1775 (1986).
Ingber, D. E., Madri, J. A. & Jamieson, J. D. Proc. natn. Acad. Sci. U.S.A. 78, 3901–3905 (1981).
Engerman, R. L., Pfaffenbach, D. & Davis, M. D. Lab. Invest. 17, 738–743 (1967).
Gotoh, M., Maki, T., T. Kiyoizumi, Satomi, S. & Monaco, A. Transplantation 40, 437–438 (1985).
Ausprunk, D. H. & Folkman, J. Microvasc. Res. 14, 53–65 (1977).
Folkman, J. & Haudenschild, C. Nature 288, 551–556 (1980).
The Pathology of Incipient Neoplasia (eds Henson, D. E. & Albores-Saavedra, J.) (Saunders, Philadelphia, 1986).
Foulds, L. Neoplastic Development (Academic, London, 1969).
Knudson, A. G. A. Rev. Genet. 20, 231–251 (1986).
Klein, G. Science 238, 1539–1545 (1987).
Srivasta, A., Laidler, P., Davies, R. P., Horgan, K. & Hughes, L. E. Am. J. Path. 133, 419–423 (1988).
Gimbrone, M. A., Jr & Gullino, P. M. Canc. Res. 36, 2611–2620 (1976).
Brem, S. S., Jensen, H. M. & Gullino, P. M. Cancer 41, 239–244 (1978).
Chodak, G. W., Haudenschild, C., Gittes, R. F. & Folkman, J. Ann. Surg. 192, 762–771 (1980).
Folkman, J., Haudenschild, C., Zetter, B.R. Proc. natn. Acad. Sci. U.S.A. 76, 5217–5221 (1979).
Montesano, R., Orci, L. & Vassalli, P. J. Cell Biol. 97, 1648–1652 (1983).
Madri, J. A. & Williams, S. K. J. Cell Biol. 97, 153–165 (1983).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Folkman, J., Watson, K., Ingber, D. et al. Induction of angiogenesis during the transition from hyperplasia to neoplasia. Nature 339, 58–61 (1989). https://doi.org/10.1038/339058a0
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/339058a0
- Springer Nature Limited
This article is cited by
-
Metabolic intervention by low carbohydrate diet suppresses the onset and progression of neuroendocrine tumors
Cell Death & Disease (2023)
-
The inhibition of protein translation promotes tumor angiogenic switch
Molecular Biomedicine (2022)
-
Targeting tumor innervation: premises, promises, and challenges
Cell Death Discovery (2022)
-
Impact of VEGFA promoter polymorphisms on esophageal cancer risk in North-West Indians: a case-control study
Genes & Genomics (2022)