Chemotherapeutic stress selectively activates NF-kappa B-dependent AKT and VEGF expression in liver cancer-derived endothelial cells.
Targeting endothelial cells (EC) that line tumor blood vessels forms the basis for metronomic therapy and is a promising new strategy for the treatment of cancer. Genetic and phenotypic differences between tumor-derived and normal ECs indicate that targeting tumor ECs may be therapeutically useful. In the present study, we examined differences in responses to chemotherapy in microvascular EC lines from tumoral (T-EC) and normal (N-EC) mouse liver tissues. The identity of these cells was confirmed by immunocytochemistry for EC markers, such as vascular endothelial-cadherin and CD31 for both types of ECs, and the tumor-endothelial-specific marker tumor endothelial marker-7 for T-EC. The involvement of Akt in NF-kappaB-dependent angiogenesis was different between N-EC and T-EC. Chemotherapeutic stress increased angiogenesis in T-EC, but not N-EC via an NF-kappaB-Akt-dependent manner. Both NF-kappaB and Akt were involved in enhanced survival and migration in T-EC in response to chemotherapeutic stress. Moreover, Akt was involved in NF-kappaB-dependent VEGF expression and angiogenesis. These studies, showing differences in cellular responses to chemotherapy in tumor-derived ECs, indicate that specific therapies targeting these cells may be therapeutically useful for liver cancers.
Meng
Fanyin
F
Dept of Internal Medicine, The Ohio State University, 514A Tzagournis Medical Research Facility, Columbus, OH 43210, USA.
Henson
Roger
R
Patel
Tushar
T
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D015820:Cadherins / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D004052:Diethylnitrosamine; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000098:blood supply / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008833:Microcirculation / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D000093542:Gemcitabine; D000099152:Cadherin 5
D015703:Antigens, CD; D000964:Antimetabolites, Antineoplastic; D015820:Cadherins; D003841:Deoxycytidine; D004052:Diethylnitrosamine; D016328:NF-kappa B; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D051057:Proto-Oncogene Proteins c-akt; D011956:Receptors, Cell Surface; D042461:Vascular Endothelial Growth Factor A; D000093542:Gemcitabine; D000099152:Cadherin 5; C509500:tumor endothelial cell marker 7, mouse; C467480:vascular endothelial growth factor A, mouse