Selection of human cervical epithelial cells that possess reduced apoptotic potential to low-oxygen conditions.
Since human papillomavirus (HPV) infection is strongly associated with cervical neoplasia and tumor hypoxia has prognostic significance in human cervical carcinomas, we examined the relationship between hypoxia and apoptosis in human cervical epithelial cells expressing high-risk HPV type 16 oncoproteins. In vitro, hypoxia stimulated both p53 induction and apoptosis in primary cervical epithelial cells infected with the HPV E6 and E7 genes but not in cervical fibroblasts infected with E6 and E7. Furthermore, cell lines derived from HPV-associated human cervical squamous cell carcinomas were substantially less sensitive to apoptosis induced by hypoxia, indicating that these cell lines have acquired additional genetic alterations that reduced their apoptotic sensitivity. Although the process of long-term cell culturing resulted in selection for subpopulations of HPV oncoprotein-expressing cervical epithelial cells with diminished apoptotic potential, the exposure of cells to hypoxia greatly accelerated the selection process. These results provide evidence for the role of hypoxia-mediated selection of cells with diminished apoptotic potential in the progression of human tumors and can in part explain why cervical tumors that possess low pO2 values are more aggressive.
Kim
C Y
CY
Department of Radiation Oncology, Stanford University School of Medicine, California 94305, USA.
Tsai
M H
MH
Osmanian
C
C
Graeber
T G
TG
Lee
J E
JE
Giffard
R G
RG
DiPaolo
J A
JA
Peehl
D M
DM
Giaccia
A J
AJ
D017209:Apoptosis; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology*; D015687:Cell Hypoxia; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D002472:Cell Transformation, Viral / Q000235:genetics; D002478:Cells, Cultured / Q000528:radiation effects; D002584:Cervix Uteri / Q000166:cytology* / Q000378:metabolism / Q000528:radiation effects; D004847:Epithelial Cells; D004848:Epithelium / Q000378:metabolism / Q000528:radiation effects; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D006801:Humans; D008954:Models, Biological; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000032:analysis; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000502:physiology; D010100:Oxygen / Q000494:pharmacology*; D027383:Papillomaviridae / Q000235:genetics*; D050725:Papillomavirus E7 Proteins; D011518:Proto-Oncogene Proteins / Q000032:analysis; D019253:Proto-Oncogene Proteins c-bcl-2; D012097:Repressor Proteins; D012641:Selection, Genetic; D014162:Transfection; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000032:analysis; D002583:Uterine Cervical Neoplasms / Q000378:metabolism / Q000473:pathology*; D051028:bcl-2-Associated X Protein
C068651:E6 protein, Human papillomavirus type 16; D009363:Neoplasm Proteins; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012097:Repressor Proteins; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; C059731:oncogene protein E7, Human papillomavirus type 16; D010100:Oxygen