Human blood late outgrowth endothelial cells for gene therapy of cancer: determinants of efficacy.
Human adult blood late outgrowth endothelial cells (BOECs) are potential yet untested cellular vehicles to target tumor-cytotoxic effectors to tumors. We show that, following intravenous injection into irradiated mice, BOECs home to Lewis lung carcinoma (LLC) lung metastases, but less so to liver or kidney metastases. BOECs targeted most but not all of the lung metastases, to a different degree. While most of the homed BOECs took up an extravascular position, some integrated into tumor vessels. Sequestration into normal tissue was low. Placental growth factor mediated both migration and invasion of BOECs into LLC spheroid masses in vitro, as did VEGF. When armed with a suicide gene, BOECs exerted a bystander effect on LLC cells in vitro and in vivo. Surprisingly, i.v. administration of armed BOECs into mice bearing multi-organ LLC metastases did not prolong survival. In addition to homing efficacy other parameters impacted upon the efficacy of BOECs. These include the ultimate susceptibility of BOECs to suicide gene-induced cell death, their paracrine proliferative effect on LLC cells and their low proliferation rate compared to LLC cells. Addressing these determinants may make BOECs a useful addition to the arsenal of tumor-targeting moieties.
Wei
J
J
University Children's Hospital, Ulm, Germany.
Jarmy
G
G
Genuneit
J
J
Debatin
K-M
KM
Beltinger
C
C
D020533:Angiogenesis Inhibitors / Q000235:genetics / Q000627:therapeutic use; D000818:Animals; D001932:Brain Neoplasms / Q000556:secondary / Q000628:therapy; D024201:Bystander Effect; D018827:Carcinoma, Lewis Lung / Q000473:pathology / Q000556:secondary* / Q000628:therapy*; D016923:Cell Death; D002469:Cell Separation; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000637:transplantation* / Q000821:virology; D005818:Genetic Engineering; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D007150:Immunohistochemistry; D016130:Immunophenotyping; D007275:Injections, Intravenous; D008175:Lung Neoplasms / Q000473:pathology / Q000556:secondary* / Q000628:therapy*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D009389:Neovascularization, Pathologic; D019899:Paracrine Communication; D000072483:Placenta Growth Factor; D011257:Pregnancy Proteins / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology
D020533:Angiogenesis Inhibitors; C000608036:PGF protein, human; C000608037:Pgf protein, mouse; D011257:Pregnancy Proteins; D042461:Vascular Endothelial Growth Factor A; D000072483:Placenta Growth Factor