SELECTION OF HUMAN CERVICAL EPITHELIAL-CELLS THAT POSSESS REDUCED APOPTOTIC POTENTIAL TO LOW-OXYGEN CONDITIONS

Since human papillomavirus (HPS') infection is strongly associated wit h cervical neoplasia and tumor hypoxia has prognostic significance in human cervical carcinomas, wa examined the relationship between hypoxi a and apoptosis in human cervical epithelial cells expressing high-ris k HPV type 16 oncoproteins. In vitro, hypoxia stimulated both p53 indu ction and apoptosis in primary cervical epithelial cells infected with the HPV ES and E7 genes hut 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 a cquired additional genetic alterations that reduced their apoptotic se nsitivity. Although the process of long-term cell culturing resulted i n 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 resu lts provide evidence for the role of hypoxia-mediated selection of cel ls with diminished apoptotic potential in tile progression of human tu mors and can in part explain why cervical tumors that possess low pO(2 ) values are more aggressive.