Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Halting angiogenesis suppresses carcinoma cell invasion

Nature Medicine volume 3, pages 1222–1227 (1997)Cite this article

Abstract

The importance of angiogenesis in malignant tumor growth has been interpreted mainly in terms of oxygen and nutrient supply. Here we demonstrate its fundamental role for tumor invasion of malignant human keratinocytes in surface transplants on nude mice. Distinct patterns of angiogenesis and vascular endothelial growth factor receptor-2 (VEGFR-2) expression allowed us to distinguish between benign and malignant cells. Functional inactivation of VEGF-R2 by a blocking antibody disrupted ongoing angiogenesis and prevented invasion of malignant cells, without reducing tumor cell proliferation. The reversion of a malignant into a benign phenotype by halting angiogenesis demonstrates a significant function of vascular endothelium for tumor invasion.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Folkman J., Watson K., Ingber D. & Hanahan D. Induction of angiogenesis during the transition from hyperplasia to neoplasia. Nature 339, 58–61 (1989).

    Article  CAS  PubMed  Google Scholar 

  2. Gimbrone, M., Leapman, S., Cotran, R. & Folkman, J. Tumor dormancy in vivo by prevention of neovascularization. J. Exp. Med. 136, 261–276 (1972).

    Article  PubMed  PubMed Central  Google Scholar 

  3. Nicosia R.F., Tchao R. & Leighton J. Interaction between newly formed endothelial channels and carcinoma cells in plasma clot culture. Clin. Exp. Metastasis 4, 91–104 (1986).

    Article  CAS  PubMed  Google Scholar 

  4. Hamada, J., Cavanaugh, P.G., Lotan, O. & Nicolson, G. Separable growth and migration factors for large-cell lymphoma cells secreted by microvascular endothelial Cells derived from target organs for metastasis. Br. J. Cancer 66, 349–354 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Rak, J.W., Filmus, J. & Kerbel, R.S. Reciprocal paracrine interactions between tumour cells and endothelial cells: The ‘angiogenesis progression’ hypothesis. Eur. J. Cancer 32A, 2438–2450 (1996).

    Article  CAS  PubMed  Google Scholar 

  6. Weidner, N. Intratumor microvessel density as a prognostic factor in cancer. Am. J. Pathol. 147, 9–15 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Liotta, L., Kleinerman, J. & Saidel F. Quantitative relationships of intravascular tumor cells, tumor vessels, and pulmonary metastases following tumor implantation. Cancer Res. 34, 997–1004 (1974).

    CAS  PubMed  Google Scholar 

  8. Larcher, F. et al. Up-regulation of vascular endothelial growth factor/vascular permeability factor in mouse skin carcinogenesis correlates with malignant progression state and activated H-ras expression levels. Cancer Res. 56, 5391–5396 (1996).

    CAS  PubMed  Google Scholar 

  9. Hanahan, D. & Folkman, J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 86, 353–364 (1996).

    Article  CAS  PubMed  Google Scholar 

  10. Christofori, G. & Hanahan, D. Molecular dissection of multistage tumorigenesis in transgenic mice. Semin. Cancer Biol. 5, 3–21 (1994).

    CAS  PubMed  Google Scholar 

  11. Brooks, P.C. et al. Antiintegrin αvβ3 blocks human breast cancer growth and angiogenesis in human skin. J. Clin. Invest. 96, 1815–1822 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Ferrara, N. & Henzel, W.J. Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells. Biochem. Biophys. Res. Commun. 161, 851–858 (1989).

    Article  CAS  PubMed  Google Scholar 

  13. Dvorak H.F., Brown L.F., Detmar, M. & Dvorak, A.M. Vascular permeability factor/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis. Am. J. Pathol. 146, 1029–1039 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Alon T. 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).

    Article  CAS  PubMed  Google Scholar 

  15. Terman B.I. & Dougher-Vermazen M. Biological properties of VEGF/VPF receptors. Cancer Metastasis Rev. 15 159–163 (1996).

    Article  CAS  PubMed  Google Scholar 

  16. Kim K.J. et al. Inhibition of vascular endothelial growth factor induced angiogenesis suppresses tumour growth in vivo. Nature 362, 841–844 (1993).

    Article  CAS  PubMed  Google Scholar 

  17. Cheng, S.-Y. et al. Suppression of glioblastoma angiogenicity and tumoriogenicity by inhibition of endogenous expression of vascular endothelial growth factor. Proc. Natl. Acad. Sci. USA 93, 8502–8507 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Millauer, B., Shawver, L.K., Plate, K.H., Risau, W. & Ullrich, A. Glioblastoma growth inhibited in vivo by a dominant-negative flk-1 mutant. Nature 367, 576–579 (1994).

    Article  CAS  PubMed  Google Scholar 

  19. Millauer, B. et al. Dominant-negative inhibition of flk-1 suppresses the growth of many tumor types in vivo. Cancer Res. 56, 1615–1620 (1996).

    CAS  PubMed  Google Scholar 

  20. Warren, R.S., Yuan, H., Matli, M.R., Gillett, N.A. & Ferrara, N. Regulation by vascular endothelial growth factor of human colon cancer tumorigenesis in a mouse model of experimental liver metastasis. J. Clin. Invest. 95, 1789–1797 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Ferrara, N. et al. Expression of vascular endothelial growth factor does not promote transformation but confers a growth advantage in vivo to Chinese hamster ovary cells. J. Clin. Invest. 91, 160–170 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Zhang, H.-T. et al. Enhancement of tumor growth and vascular density by transfection of vascular endothelial cell growth factor into MCF-7 human breast carcinoma cells. J. Natl. Cancer Inst. 87, 213–219 (1995).

    Article  CAS  PubMed  Google Scholar 

  23. Claffey, K.P. et al. Expression of vascular permeability factor/vascular endothelial growth factor by melanoma cells increases tumor growth, angiogenesis and experimental metastasis. Cancer Res. 56, 172–181 (1996).

    CAS  PubMed  Google Scholar 

  24. Detmar, M. Molecular regulation of angiogenesis in the skin. J. Invest. Dermatol. 106, 207–208 (1996).

    Article  CAS  PubMed  Google Scholar 

  25. Boukamp, P. et al. Normal keratinization in a spontaneously immortalized aneuploid human keratinocyte cell line. J. Cell Biol. 106, 761–771 (1988).

    Article  CAS  PubMed  Google Scholar 

  26. Boukamp, P., Stanbridge, E.J., Foo, D.Y., Cerutti, P.A. & Fusenig, N.E. c-Ha-ras oncogene expression in immortalized human keratinocytes (HaCaT) alters growth potential in vivo but lacks correlation with malignancy. Cancer Res. 50, 2840–2847 (1990).

    CAS  PubMed  Google Scholar 

  27. Boukamp, P. et al. Step-wise progression in human skin carcinogenesis in vitro involves mutational inactivation of p53, rasH oncogene activation and additional chromosome loss. Oncogene 11, 961–969 (1995).

    CAS  PubMed  Google Scholar 

  28. Fusenig, N.E., Breitkreutz, D., Bohnert, A. & Mackenzie, I.C. Epithelial-mesenchymal interactions in tissue homeostasis and malignant transformation. in: Oral Cancer (ed. Johnson, N. W.) 218–248 (Cambridge Univ. Press, Cambridge, 1991).

    Google Scholar 

  29. Breitkreutz, D. et al. Epidermal morphogenesis and keratin expression in c-Ha-ras-transfected tumorigenic clones of the human HaCaT cell line. Cancer Res. 51, 4402–4409 (1991).

    CAS  PubMed  Google Scholar 

  30. Rockwell, P., Neufeld, G., Classman, A., Caron, D. & Goldstein, N. In vitro neutralization of vascular endothelial growth factor activation of flk-1 by a monoclonal antibody. Mol. Cell Differ. 3(1) 91–109 (1995).

    CAS  Google Scholar 

  31. Saez, E. et al. C-fos is required for malignant progression of skin tumors. Cell 82, 721–732 (1995).

    Article  CAS  PubMed  Google Scholar 

  32. Parangi, S. et al. Antiangiogenic therapy of transgenic mice impairs de novo tumor growth. Proc. Natl. Acad. Sci. USA 93, 2002–2007 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Relf M. et al. Expression of the angiogenic factors vascular endothelial cell growth factor, acidic and basic fibroblast growth factor, tumor growth factor 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 (1997).

    CAS  PubMed  Google Scholar 

  34. Mandriota, S.J., Menoud, A.-P. & Pepper, M.S. Transforming growth factor β1 downregulates vascular endothelial growth factor receptor 2/flk-1 in vascular endothelial cells. J. Biol. Chem. 271, 11500–11505 (1996).

    Article  CAS  PubMed  Google Scholar 

  35. Patterson, C. et al. Downregulation of vascular endothelial growth factor receptors by tumor necrosis factor a in cultured human vascular endothelial cells. J. Clin. Invest. 98, 490–496 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Yoshida, A., Anandapte, B. & Zetter, B.R. Differential endothelial migration and proliferation to basic fibroblast growth factor and vascular endothelial growth factor. Growth Factors 13, 57–64 (1996).

    Article  CAS  PubMed  Google Scholar 

  37. Holmgren, L., O'Reilly, M.S. & Folkman, J. Dormancy of micrometastases: Balanced proliferation and apoptosis in the presence of angiogenesis suppression. Nature Med 1, 149–153 (1995).

    Article  CAS  PubMed  Google Scholar 

  38. Tischer, E. et al. The human gene for vascular endothelial growth factor: Multiple protein forms are encoded through alternative exon splicing. J. Biol. Chem. 266, 11947–11954 (1991).

    CAS  PubMed  Google Scholar 

  39. Millauer, B. et al. High affinity VEGF binding and developmental expression suggest flk-1 as a major regulator of vasculogenesis and angiogenesis. Cell 72, 835–846 (1993).

    Article  CAS  PubMed  Google Scholar 

  40. Moorman, A.F.M., De-Boer, P.A.J., Vermeulen, J. Vermeulen, J.L.M. Lamers W.H. Practical aspects of radio-isotopic in situ hybridization on RNA. Histochem. J. 25, 251–266 (1992).

    Article  Google Scholar 

Download references

Author information

Author notes

  1. Mihaela Skobe

    Present address: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Research North, 99 Brookline Avenue, Boston, Massachusetts, 02215, USA

Authors and Affiliations

  1. Division of Carcinogenesis and Differentiation, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany

    Mihaela Skobe, Silvia Vosseler & Norbert E. Fusenig

  2. Department of Immunology, ImClone Systems Inc.,, 180 Varick Street, New York, New York, 10014, USA

    Patricia Rockwell & Neil Goldstein

Authors
  1. Mihaela Skobe
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Patricia Rockwell
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Neil Goldstein
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Silvia Vosseler
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Norbert E. Fusenig
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Skobe, M., Rockwell, P., Goldstein, N. et al. Halting angiogenesis suppresses carcinoma cell invasion. Nat Med 3, 1222–1227 (1997). https://doi.org/10.1038/nm1197-1222

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm1197-1222

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

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