HIF-1alpha attenuates tumor growth in spite of augmented vascularization in an A549 adenocarcinoma mouse model.
The hypoxia-inducible transcription factor, HIF-1, adapts cells to low oxygen tension. In addition to the activation of angiogenesis by induction of VEGF, HIF-1 may trigger hypoxia-induced growth arrest and apoptosis. The aim of this study was to analyze the overall effect of HIF-1 on tumor growth in a mouse model, employing human lung adenocarcinoma A549 cells. The A549 cells were transfected to overexpress HIF-1alpha. These cells displayed decreased proliferation, cell-cycle entry, colony formation in soft agar and elevated levels of apoptosis, when compared to control cells transfected with empty vector. The cells were employed in a tumor model by subcutaneous injection into CD-1 nude mice. Persistent overexpression of HIF1alpha and VEGF was demonstrated in these tumors. The HIF-1alpha-overexpressing tumors displayed less tumor growth when compared to tumors formed by control cells. Tumors derived from HIF-1alpha-overexpressing cells revealed an increase in apoptosis when compared to control tumors, in spite of a marked increase in vascular density. We conclude that in lung A549 cells, overexpression of HIF-1alpha negatively affects tumor growth due to decreased proliferation and increased apoptosis, despite augmented angiogenesis.
Savai
Rajkumar
R
Department of Internal Medicine II, Medical School of the Justus-Liebig-University, D-35392 Giessen, Germany.
Schermuly
Ralph Theo
RT
Voswinckel
Robert
R
Renigunta
Aparna
A
Reichmann
Bernd
B
Eul
Bastian
B
Grimminger
Friedrich
F
Seeger
Werner
W
Rose
Frank
F
Hänze
Jörg
J
D000230:Adenocarcinoma / Q000098:blood supply / Q000235:genetics / Q000473:pathology*; D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D006801:Humans; D020287:In Situ Nick-End Labeling; D008175:Lung Neoplasms / Q000098:blood supply / Q000235:genetics / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis; D023041:Xenograft Model Antitumor Assays / Q000379:methods*
D042461:Vascular Endothelial Growth Factor A