Embryonic endothelial progenitor cells armed with a suicide gene target hypoxic lung metastases after intravenous delivery.
We show that mouse embryonic endothelial progenitor cells (eEPCs) home preferentially to hypoxic lung metastases when administered intravenously. This specificity is inversely related to the degree of perfusion and vascular density in the metastasis and directly related to local levels of hypoxia and VEGF. Ex vivo expanded eEPCs that were genetically modified with a suicide gene specifically and efficiently eradicated lung metastases with scant patent blood vessels. eEPCs do not express MHC I proteins, are resistant to natural killer cell-mediated cytolysis, and can contribute to tumor vessel formation also in nonsyngeneic mice. These results indicate that eEPCs can be used in an allogeneic setting to treat hypoxic metastases that are known to be resistant to conventional therapeutic regimes.
Wei
Jiwu
J
University Children's Hospital, Ulm D-89075, Germany.
Blum
Sabine
S
Unger
Marcus
M
Jarmy
Gergely
G
Lamparter
Mathias
M
Geishauser
Albert
A
Vlastos
Georgios A
GA
Chan
Gordon
G
Fischer
Klaus-Dieter
KD
Rattat
Dirk
D
Debatin
Klaus-Michael
KM
Hatzopoulos
Antonis K
AK
Beltinger
Christian
C
D000818:Animals; D001859:Bone Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D024201:Bystander Effect; D018827:Carcinoma, Lewis Lung / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D015687:Cell Hypoxia; D043525:Cytosine Deaminase / Q000235:genetics / Q000378:metabolism; D005314:Embryonic and Fetal Development / Q000502:physiology*; D004730:Endothelium, Vascular / Q000196:embryology* / Q000378:metabolism; D005472:Fluorouracil / Q000378:metabolism; D018390:Gene Targeting; D041722:Genes, Transgenic, Suicide; D015316:Genetic Therapy; D005822:Genetic Vectors; D007275:Injections, Intravenous; D007694:Killer Cells, Natural / Q000378:metabolism; D008175:Lung Neoplasms / Q000378:metabolism / Q000556:secondary* / Q000628:therapy*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D012516:Osteosarcoma / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D010430:Pentosyltransferases / Q000235:genetics / Q000378:metabolism; D011355:Prodrugs / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000494:pharmacology; D013234:Stem Cells / Q000502:physiology*; D015996:Survival Rate; D014498:Uracil / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D011355:Prodrugs; D011993:Recombinant Fusion Proteins; D042461:Vascular Endothelial Growth Factor A; D014498:Uracil; D010430:Pentosyltransferases; C023269:uracil phosphoribosyltransferase; D043525:Cytosine Deaminase; D005472:Fluorouracil