Targeting exogenous genes to tumor angiogenesis by transplantation of genetically modified hematopoietic stem cells.
Angiogenic tumor vessels are promising targets for the activity and the selective delivery of cancer therapeutics. The bone marrow contributes different cell types to the tumor stroma, including hematopoietic cells and, as recently suggested, vascular endothelial cells (ECs). 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 gene. 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.
De Palma
Michele
M
Laboratory for Gene Transfer and Therapy, IRCC, Institute for Cancer Research and Treatment, University of Torino Medical School, Strada Provinciale 142, 10060 Candiolo, Torino, Italy.
Venneri
Mary Anna
MA
Roca
Cristina
C
Naldini
Luigi
L
D000818:Animals; D015415:Biomarkers; D016026:Bone Marrow Transplantation; D005260:Female; D018390:Gene Targeting; D017930:Genes, Reporter; D015316:Genetic Therapy; D005822:Genetic Vectors; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D006801:Humans; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000098:blood supply* / Q000628:therapy; D009389:Neovascularization, Pathologic; D010641:Phenotype; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D042787:Receptor, TIE-2; D014161:Transduction, Genetic; D014407:Tumor Cells, Cultured
D015415:Biomarkers; D020794:Receptor Protein-Tyrosine Kinases; D042787:Receptor, TIE-2