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Targeting exogenous genes to tumor angiogenesis by transplantation of genetically modified hematopoietic stem cells

Abstract

Angiogenic tumor vessels are promising targets for the activity and the selective delivery of cancer therapeutics1,2. The bone marrow contributes different cell types to the tumor stroma, including hematopoietic cells3,4 and, as recently suggested, vascular endothelial cells (ECs)5. Thus, transplantation of genetically modified bone marrow progenitors may represent a vehicle for the transport of gene therapy to tumors. We transduced bone marrow progenitors with lentiviral vectors expressing genes from transcription-regulatory elements of Tie2/Tek gene6. When tumors were grown in the transplanted mice, the new vector marked a distinct hematopoietic population that 'homed' to the tumor and closely interacted with vascular ECs at the tumor periphery. These Tie2-expressing mononuclear (TEM) cells had a distinguishable phenotype and were present selectively at angiogenic sites. Unexpectedly, we did not find bone marrow–derived ECs in tumor vessels when we transplanted bone marrow progenitors constitutively expressing a marker gene from the Tie2 or ubiquitously active promoters. By delivering a 'suicide' gene, we selectively eliminated the TEM cells and achieved substantial inhibition of angiogenesis and slower tumor growth without systemic toxicity. Thus, TEM cells may account for the proangiogenic activity of bone marrow–derived cells in tumors, may represent a new target for drug development and may provide the means for selective gene delivery and targeted inhibition of tumor angiogenesis.

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Figure 1: Recruitment of transduced bone marrow–derived cells to the tissues of transplanted mice and restricted expression of the Tie2p/e vector.
Figure 2: The Tie2p/e-GFP-positive cells in tumors were hematopoietic with a distinguishable phenotype, closely interacting with but distinct from ECs.
Figure 3: Selective in vivo elimination of the Tie2p/e-vector-targeted cells inhibited tumor angiogenesis and slowed tumor growth.

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Acknowledgements

We thank F. Bussolino, U. Deutsch, C. Bonini and P.L. Lollini for providing reagents; U. Merle for help with partial hepatectomies; L.E. Ailles for help with bone marrow transplantation; G. De Rosa for pathology and A. Sottile for blood cell counts; M. Geuna for help with flow cytometry; L. Sergi Sergi, D. Milne, P. Ferrero, G. Carchia, R. Lonoce and R. Albano for technical help; and L. Trusolino and E.M. Wright for reading the manuscript. C.R. is a recipient of a Fondazione Italiana per la Ricerca sul Cancro fellowship. This research was supported by grants from Associazione Italiana per la Ricerca sul Cancro (23-2001), Telethon (A143), the Italian Ministries of Scientific Research (2002054797) and Health, the European Union (QLK3-1999-00859), Compagnia di San Paolo and Cell Genesys to L.N.

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Correspondence to Luigi Naldini.

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De Palma, M., Venneri, M., Roca, C. et al. Targeting exogenous genes to tumor angiogenesis by transplantation of genetically modified hematopoietic stem cells. Nat Med 9, 789–795 (2003). https://doi.org/10.1038/nm871

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