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:

Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of vascular endothelial growth factor

Nature Medicine volume 8, pages 128–135 (2002)Cite this article

Abstract

Conventional immunosuppressive drugs have been used effectively to prevent immunologic rejection in organ transplantation. Individuals taking these drugs are at risk, however, for the development and recurrence of cancer. In the present study we show that the new immunosuppressive drug rapamycin (RAPA) may reduce the risk of cancer development while simultaneously providing effective immunosuppression. Experimentally, RAPA inhibited metastatic tumor growth and angiogenesis in in vivo mouse models. In addition, normal immunosuppressive doses of RAPA effectively controlled the growth of established tumors. In contrast, the most widely recognized immunosuppressive drug, cyclosporine, promoted tumor growth. From a mechanistic perspective, RAPA showed antiangiogenic activities linked to a decrease in production of vascular endothelial growth factor (VEGF) and to a markedly inhibited response of vascular endothelial cells to stimulation by VEGF. Thus, the use of RAPA, instead of cyclosporine, may reduce the chance of recurrent or de novo cancer in high-risk transplant patients.

Access through your institution
Buy or subscribe

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

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

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

Figure 1: Rapamycin inhibits, whereas CsA promotes, metastatic tumor growth in liver.
Figure 2: Rapamycin inhibits tumor angiogenesis, whereas CsA stimulates tumor neovascularization.
Figure 3: CT-26 tumors in transparent chambers are markedly smaller and have less vascularization with rapamycin compared to CsA treatment.
Figure 4: Rapamycin causes a decrease in VEGF production that correlates with reduced VEGF mRNA.
Figure 5: Rapamycin inhibits tumor cell proliferation and VEGF-dependent HUVEC proliferation and tubular formation.
Figure 6: Rapamycin treatment controls the growth of tumors in mice.

Similar content being viewed by others

References

  1. Garver, R.I. Jr. et al. Recurrence of bronchioloalveolar carcinoma in transplanted lungs. N. Engl. J. Med. 340, 1071–1074 (1999).

    Article  PubMed  Google Scholar 

  2. Meyer, C.G., Penn, I. & James, L. Liver transplantation for cholangiocarcinoma: results in 207 patients. Transplantation 69, 1633–1637 (2000).

    Article  CAS  PubMed  Google Scholar 

  3. Penn, I. Occurrence of cancers in immunosuppressed organ transplant recipients. Clin. Transpl. 147–158 (1998).

  4. Dumont, F.J., Staruch, M.J., Koprak, S.L., Melino, M.R. & Sigal, N.H. Distinct mechanisms of suppression of murine T cell activation by the related macrolides FK-506 and rapamycin. J. Immunol. 144, 251–258 (1990).

    CAS  PubMed  Google Scholar 

  5. Sehgal, S.N. Rapamune (RAPA, rapamycin, sirolimus): mechanism of action immunosuppressive effect results from blockade of signal transduction and inhibition of cell cycle progression. Clin. Biochem. 31, 335–340 (1998).

    Article  CAS  PubMed  Google Scholar 

  6. Wiederrecht, G.J. et al. Mechanism of action of rapamycin: new insights into the regulation of G1-phase progression in eukaryotic cells. Prog. Cell Cycle Res. 1, 53–71 (1995).

    Article  CAS  PubMed  Google Scholar 

  7. Kahan, B.D. Efficacy of sirolimus compared with azathioprine for reduction of acute renal allograft rejection: a randomised multicentre study. The Rapamune US Study Group. Lancet 356, 194–202 (2000).

    Article  CAS  PubMed  Google Scholar 

  8. Shapiro, A.M. et al. Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N. Engl. J. Med. 343, 230–238 (2000).

    Article  CAS  PubMed  Google Scholar 

  9. Schreiber, S.L. & Crabtree, G.R. The mechanism of action of cyclosporin A and FK506. Immunol. Today 13, 136–142 (1992).

    Article  CAS  PubMed  Google Scholar 

  10. Ondrus, D. et al. The incidence of tumours in renal transplant recipients with long-term immunosuppressive therapy. Int. Urol. Nephrol. 31, 417–422 (1999).

    Article  CAS  PubMed  Google Scholar 

  11. Zhong, H. et al. Modulation of hypoxia-inducible factor 1α expression by the epidermal growth factor/phosphatidylinositol 3-kinase/PTEN/AKT/FRAP pathway in human prostate cancer cells: implications for tumor angiogenesis and therapeutics. Cancer Res. 60, 1541–1545 (2000).

    CAS  PubMed  Google Scholar 

  12. Semenza, G.L. Regulation of mammalian O2 homeostasis by hypoxia-inducible factor 1. Annu. Rev. Cell Dev. Biol. 15, 551–578 (1999).

    Article  CAS  PubMed  Google Scholar 

  13. Sanchez-Elsner, T. et al. Synergistic cooperation between hypoxia and transforming growth factor-β pathways on human vascular endothelial growth factor gene expression. J. Biol. Chem. 38527–38535 (2001).

  14. Schwarte-Waldhoff, I. et al. Smad4/DPC4-mediated tumor suppression through suppression of angiogenesis. Proc. Natl. Acad. Sci. USA 97, 9624–9629 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Zheng, W., Seftor, E.A., Meininger, C.J., Hendrix, M.J. & Tomanek, R.J. Mechanisms of coronary angiogenesis in response to stretch: role of VEGF and TGF-β. Am. J. Physiol. Heart Circ. Physiol. 280, H909–H917 (2001).

    Article  CAS  PubMed  Google Scholar 

  16. Carmeliet, P. & Jain, R.K. Angiogenesis in cancer and other diseases. Nature 407, 249–257 (2000).

    Article  CAS  PubMed  Google Scholar 

  17. Guba, M. et al. A primary tumor promotes dormancy of solitary tumor cells before inhibiting angiogenesis. Cancer Res. 61, 5575–5579 (2001).

    CAS  PubMed  Google Scholar 

  18. Eng, C.P., Sehgal, S.N. & Vezina, C. Activity of rapamycin (AY-22,989) against transplanted tumors. J. Antibiot. (Tokyo) 37, 1231–1237 (1984).

    Article  CAS  Google Scholar 

  19. Asaishi, K., Endrich, B., Gotz, A. & Messmer, K. Quantitative analysis of microvascular structure and function in the amelanotic melanoma A-Mel-3. Cancer Res. 41, 1898–1904 (1981).

    CAS  PubMed  Google Scholar 

  20. Fukumura, D., Yuan, F., Monsky, W.L., Chen, Y. & Jain, R.K. Effect of host microenvironment on the microcirculation of human colon adenocarcinoma. Am. J. Pathol. 151, 679–688 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  22. Ferrara, N. The role of vascular endothelial growth factor in pathological angiogenesis. Breast Cancer Res. Treat. 36, 127–137 (1995).

    Article  CAS  PubMed  Google Scholar 

  23. Vinals, F., Chambard, J.C. & Pouyssegur, J. p70 S6 kinase–mediated protein synthesis is a critical step for vascular endothelial cell proliferation. J. Biol. Chem. 274, 26776–26782 (1999).

    Article  CAS  PubMed  Google Scholar 

  24. Yu, Y. & Sato, J.D. MAP kinases, phosphatidylinositol 3-kinase, and p70 S6 kinase mediate the mitogenic response of human endothelial cells to vascular endothelial growth factor. J. Cell Physiol. 178, 235–246 (1999).

    Article  CAS  PubMed  Google Scholar 

  25. Ilan, N., Mahooti, S. & Madri, J.A. Distinct signal transduction pathways are utilized during the tube formation and survival phases of in vitro angiogenesis. J. Cell Sci. 111, 3621–3631 (1998).

    Article  CAS  PubMed  Google Scholar 

  26. Dayanir, V., Meyer, R.D., Lashkari, K. & Rahimi, N. Identification of tyrosine residues in vascular endothelial growth factor receptor-2/FLK-1 involved in activation of phosphatidylinositol 3-kinase and cell proliferation. J. Biol. Chem. 276, 17686–17692 (2001).

    Article  CAS  PubMed  Google Scholar 

  27. Browder, T. et al. Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drug–resistant cancer. Cancer Res. 60, 1878–1886 (2000).

    CAS  PubMed  Google Scholar 

  28. Folkman, J., Browder, T. & Palmblad, J. Angiogenesis research: guidelines for translation to clinical application. Thromb. Haemost. 86, 23–33 (2001).

    Article  CAS  PubMed  Google Scholar 

  29. Klement, G. et al. Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicity. J. Clin. Invest 105, R15–R24 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Gohongi, T. et al. Tumor-host interactions in the gallbladder suppress distal angiogenesis and tumor growth: involvement of transforming growth factor β1. Nature Med. 5, 1203–1208 (1999).

    Article  CAS  PubMed  Google Scholar 

  31. Iurlaro, M. et al. Antiangiogenesis by cyclosporine. Exp. Hematol. 26, 1215–1222 (1998).

    CAS  PubMed  Google Scholar 

  32. Benelli, U., Ross, J.R., Nardi, M. & Klintworth, G.K. Corneal neovascularization induced by xenografts or chemical cautery. Inhibition by cyclosporin A. Invest. Ophthalmol. Vis. Sci. 38, 274–282 (1997).

    CAS  PubMed  Google Scholar 

  33. Hojo, M. et al. Cyclosporine induces cancer progression by a cell-autonomous mechanism. Nature 397, 530–534 (1999).

    Article  CAS  PubMed  Google Scholar 

  34. Brattain, M.G., Strobel-Stevens, J., Fine, D., Webb, M. & Sarrif, A.M. Establishment of mouse colonic carcinoma cell lines with different metastatic properties. Cancer Res. 40, 2142–2146 (1980).

    CAS  PubMed  Google Scholar 

  35. Saunders, R.N., Metcalfe, M.S. & Nicholson, M.L. Rapamycin in transplantation: a review of the evidence. Kidney Int. 59, 3–16 (2001).

    Article  CAS  PubMed  Google Scholar 

  36. Drixler, T.A. et al. Continuous administration of angiostatin inhibits accelerated growth of colorectal liver metastases after partial hepatectomy. Cancer Res. 60, 1761–1765 (2000).

    CAS  PubMed  Google Scholar 

  37. Guba, M. et al. Differential effects of short-term ACE- and AT1-receptor inhibition on postischemic injury and leukocyte adherence in vivo and in vitro. Shock 13, 190–196 (2000).

    Article  CAS  PubMed  Google Scholar 

  38. Bruns, C.J. et al. Vascular endothelial growth factor is an in vivo survival factor for tumor endothelium in a murine model of colorectal carcinoma liver metastases. Cancer 89, 488–499 (2000).

    Article  CAS  PubMed  Google Scholar 

  39. Salomon-Nhuyen, F. et al. The t(1;12)(q21;p13) translocation of human acute myeloblastic leukemia results in a TEL–ARNT fusion. Proc. Natl. Acad. Sci. USA 97, 6557–6762 (2000).

    Google Scholar 

  40. Hajitou, A. et al. Down-regulation of vascular endothelial growth factor by tissue inhibitor of metalloproteinase-2: effect on in vivo mammary tumor growth and angiogenesis. Cancer Res. 61, 3450–3457 (2001).

    CAS  PubMed  Google Scholar 

  41. Overbergh, L., Valckx, D., Waer, M. & Mathieu, C. Quantification of murine cytokine mRNAs using real time quantitative reverse transcriptase PCR. Cytokine 11, 305–312 (1999).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank M. Cetto, E. Frank, B. Schwarz, C. Graeb, S. Tange and I. Iesalnieks for excellent technical assistance. This research was supported by grants from the Roche Organ Transplantation Research Foundation, the Deutsche Forschungsgemeinschaft (STE 960/1) and the REFORM A and B programs of the University of Regensburg.

Author information

Authors and Affiliations

  1. Department of Surgery, University of Regensburg, Regensburg, Germany

    Markus Guba, Philipp von Breitenbuch, Markus Steinbauer, Gudrun Koehl, Stefanie Flegel, Matthias Hornung, Christiane J. Bruns, Carl Zuelke, Stefan Farkas, Matthias Anthuber, Karl-Walter Jauch & Edward K. Geissler

Authors
  1. Markus Guba
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Philipp von Breitenbuch
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Markus Steinbauer
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Gudrun Koehl
    View author publications

    You can also search for this author inPubMed Google Scholar

  5. Stefanie Flegel
    View author publications

    You can also search for this author inPubMed Google Scholar

  6. Matthias Hornung
    View author publications

    You can also search for this author inPubMed Google Scholar

  7. Christiane J. Bruns
    View author publications

    You can also search for this author inPubMed Google Scholar

  8. Carl Zuelke
    View author publications

    You can also search for this author inPubMed Google Scholar

  9. Stefan Farkas
    View author publications

    You can also search for this author inPubMed Google Scholar

  10. Matthias Anthuber
    View author publications

    You can also search for this author inPubMed Google Scholar

  11. Karl-Walter Jauch
    View author publications

    You can also search for this author inPubMed Google Scholar

  12. Edward K. Geissler
    View author publications

    You can also search for this author inPubMed Google Scholar

Corresponding authors

Correspondence to Markus Guba or Edward K. Geissler.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Guba, M., von Breitenbuch, P., Steinbauer, M. et al. Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of vascular endothelial growth factor. Nat Med 8, 128–135 (2002). https://doi.org/10.1038/nm0202-128

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm0202-128

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