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A tumor-homing peptide with a targeting specificity related to lymphatic vessels

Nature Medicine volume 8, pages 751–755 (2002)Cite this article

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Abstract

Blood vessels of tumors carry specific markers that are usually angiogenesis-related1,2. We previously used phage-displayed peptide libraries in vivo to identify peptides that home to tumors through the circulation and that specifically bind to the endothelia of tumor blood vessels3,4. Here we devised a phage screening procedure that would favor tumor-homing to targets that are accessible to circulating phage, but are not blood vessels. Screening on MDA-MB-435 breast carcinoma xenografts yielded multiple copies of a phage that displays a cyclic 9-amino-acid peptide, LyP-1. Homing and binding to tumor-derived cell suspensions indicated that LyP-1 also recognizes an osteosarcoma xenograft, and spontaneous prostate and breast cancers in transgenic mice, but not two other tumor xenografts. Fluorescein-labeled LyP-1 peptide was detected in tumor structures that were positive for three lymphatic endothelial markers and negative for three blood vessel markers. LyP-1 accumulated in the nuclei of the putative lymphatic cells, and in the nuclei of tumor cells. These results suggest that tumor lymphatics carry specific markers and that it may be possible to specifically target therapies into tumor lymphatics.

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Figure 1: Tumor homing and binding of LyP-1 phage, and nuclear translocation of synthetic LyP-1 peptide.
Figure 2: LyP-1 phage and LyP-1 peptide do not colocalize with blood vessel markers.
Figure 3: Colocalization of LyP-1 with lymphatic markers.

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Change history

  • 01 July 2002

    The supplementary info pieces that originally went up with the aop had incorrect figure legends. Editorial Production supplied new pieces and we put them up with the July issue.

References

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

    Article  CAS  Google Scholar 

  2. Ruoslahti, E. Specialization of tumour vasculature. Nature Rev. Cancer 2, 83–90 (2002).

    Article  Google Scholar 

  3. Arap, W., Pasqualini, R. & Ruoslahti, E. Cancer treatment by targeted drug delivery to tumor vasculature in a mouse model. Science 279, 377–380 (1998).

    Article  CAS  Google Scholar 

  4. Porkka, K., Laakkonen, P., Hoffman, J.A., Bernasconi, M. & Ruoslahti, E. A fragment of the HMGN2 protein homes to the nuclei of tumor cells and tumor endothelial cells in vivo. Proc. Natl. Acad. Sci. USA (in the press).

  5. Hoffman, J.A., Laakkonen, P., Porkka, K., Bernasconi, M. & Ruoslahti, E. In vivo and ex vivo selections using phage-displayed libraries. in Phage Display: A Practical Approach (eds. Clackson, T. & Lowman, H.) (Oxford University Press, Oxford, UK, in the press).

  6. Oliver, G. & Detmar, M. The rediscovery of the lymphatic system: old and new insights into the development and biological function of the lymphatic vasculature. Genes Dev. 16, 773–783 (2002).

    Article  CAS  Google Scholar 

  7. Makinen, T. et al. Isolated lymphatic endothelial cells transduce growth, survival and migratory signals via the VEGF-C/D receptor VEGFR-3. EMBO J. 20, 4762–4773 (2001).

    Article  CAS  Google Scholar 

  8. Chang, Y.S. et al. Mosaic blood vessels in tumors: frequency of cancer cells in contact with flowing blood. Proc. Natl. Acad. Sci.USA 97, 14608–14613 (2000).

    Article  CAS  Google Scholar 

  9. Jackson, D.G., Prevo, R., Clasper, S. & Banerji, S. LYVE-1, the lymphatic system and tumor lymphangiogenesis. Trends Immunol. 22, 317–321 (2001).

    Article  CAS  Google Scholar 

  10. Prevo, R., Banerji, S., Ferguson, D.J., Clasper, S. & Jackson, D.G. Mouse LYVE-1 is an endocytic receptor for hyaluronan in lymphatic endothelium. J. Biol. Chem. 276, 19420–19430 (2001).

    Article  CAS  Google Scholar 

  11. Breiteneder-Geleff, S. et al. Angiosarcomas express mixed endothelial phenotypes of blood and lymphatic capillaries: Podoplanin as a specific marker for lymphatic endothelium. Am. J. Pathol. 154, 385–394 (1999).

    Article  CAS  Google Scholar 

  12. Kubo, H. et al. Involvement of vascular endothelial growth factor receptor-3 in maintenance of integrity of endothelial cell lining during tumor angiogenesis. Blood 96, 546–553 (2000).

    CAS  Google Scholar 

  13. Stacker, S.A. et al. VEGF-D promotes the metastatic spread of tumor cells via the lymphatics. Nature Med. 7, 186–191 (2001).

    Article  CAS  Google Scholar 

  14. Skobe, M. et al. Induction of tumor lymphangiogenesis by VEGF-C promotes breast cancer metastasis. Nature Med. 7, 192–198 (2001).

    Article  CAS  Google Scholar 

  15. Beasley, N.J.P. et al. Intratumoral lymphangiogenesis and lymph node metastasis in head and neck cancer. Cancer Res. 62, 1315–1320 (2002).

    CAS  Google Scholar 

  16. Mandriota, S.J. et al. Vascular endothelial growth factor-C-mediated lymphangiogenesis promotes tumour metastasis. EMBO J. 20, 672–682 (2001).

    Article  CAS  Google Scholar 

  17. Leu, A.J., Berk, D.A., Lymboussaki, A., Alitalo, K. & Jain, R.K. Absence of functional lymphatics within a murine sarcoma: a molecular and functional evaluation. Cancer Res. 60, 4324–4327 (2000).

    CAS  Google Scholar 

  18. Karpanen, T. et al. Vascular endothelial growth factor C promotes tumor lymphangiogenesis and intralymphatic tumor growth. Cancer Res. 61, 1786–1790 (2001).

    CAS  Google Scholar 

  19. Carreira, C.M. et al. LYVE-1 is not restricted to the lymph vessels: Expression in normal liver blood sinusoids and down-regulation in human liver cancer and cirrhosis. Cancer Res. 61, 8079–8084 (2001).

    CAS  Google Scholar 

  20. Valtola, R. et al. VEGFR-3 and its ligand VEGF-C are associated with angiogenesis in breast cancer. Am. J. Pathol. 154, 1381–1390 (1999).

    Article  CAS  Google Scholar 

  21. Maniotis, A.J. et al. Vascular channel formation by human melanoma cells in vivo and in vitro: Vasculogenic mimicry. Am. J. Pathol. 155, 739–752 (1999).

    Article  CAS  Google Scholar 

  22. Brooks, P.C. et al. Integrin αvβ3 antagonists promote tumor regression by inducing apoptosis of angiogenic blood vessels. Cell 79, 1157–1164 (1994).

    Article  CAS  Google Scholar 

  23. St Croix, B. et al. Genes expressed in human tumor endothelium. Science 289, 1197–202 (2000).

    Article  CAS  Google Scholar 

  24. Smith, G.P. & Scott, J.K. Libraries of peptides and proteins displayed on filamentous phage. Methods Enzymol. 217, 228–257 (1993).

    Article  CAS  Google Scholar 

  25. Wender, P.A. et al. The design, synthesis, and evaluation of molecules that enable or enhance cellular uptake: peptoid molecular transporters. Proc. Natl. Acad. Sci. USA 97, 13003–13008 (2000).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank E. Engvall and E. Pasquale for comments on the manuscript; K. Alitalo, H. Kubo, T. Petrova and M. Quintanilla for antibodies; M. Bernasconi and A. Man for tumor materials; F. Ferrer for peptide synthesis; and R. Newlin for assistance with histology. This study was supported by grants CA74238, CA82715, the Cancer Center Support Grant CA 30199 from the NCI, and grant 99-3339 from the Komen Foundation. P.L. is supported by fellowship 69768 from the Academy of Finland and a fellowship from the Finnish Cultural Foundation. J.A.H. is a recipient of a National Cancer Institute Training Grant fellowship in the Molecular Pathology of Cancer.

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Authors and Affiliations

  1. Cancer Research Center, The Burnham Institute, La Jolla, California, USA

    Pirjo Laakkonen, Kimmo Porkka & Erkki Ruoslahti

  2. The Burnham Institute and Department of Pathology, Program in Molecular Pathology, University of California San Diego School of Medicine, La Jolla, California, USA

    Jason A. Hoffman

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  1. Pirjo Laakkonen
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Correspondence to Erkki Ruoslahti.

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Supplementary information

Supplementary Fig. A (PDF 262 kb)

Supplementary Fig. B

The legends to the Supplementary Figures A and B that were originally published AOP on 10 June 2002, were inadvertantly transposed. The present version of the figures is correct. (PDF 615 kb)

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Laakkonen, P., Porkka, K., Hoffman, J. et al. A tumor-homing peptide with a targeting specificity related to lymphatic vessels. Nat Med 8, 751–755 (2002). https://doi.org/10.1038/nm720

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