Isolation, Characterization, and Potential Role of Cervical Stem Cells in HPV-induced Cervical Carcinogenesis

Convincing evidence exists that persistent infection with high risk HPVs is a necessary state for the emergence of cervical cancer. However, the crucial factors determining HPV persistence and development of precancerous and cancerous lesions are largely unknown. Our study was based on the hypothesis that viral persistence and subsequent initiation of cervical carcinogenesis may only arise from infection of cervical stem cells. We report on the successful isolation of a minor subpopulation of putative cervical stem cells with expression of distinct cell surface and common stem cell markers. These undifferentiated cells possess characteristics and functional properties expected for epithelial stem cells, such as an immature cell morphology, telomerase activity, quiescence, slow cell cycle, and rapid onset of proliferation after removal from their microenvironment, correlating with a significantly increased colony formation efficiency. Virtually all of these putative stem cells have an 80-fold higher binding capacity for papillomavirus like particles. Development of an organotypic cervical explant model provided the basis for monitoring the course of infection after exposure to high risk HPV pseudoviruses within the regenerating epithelium and showed persistence of infection over time in only a small number of cells of the basal cell layer. Our studies permit the first time phenotypic and functional distinction of viable candidate cervical stem cells. Our data indicate that infection of this cell type is indeed a prerequisite to establish long-term infection. These findings represent an important step forward to thoroughly define the role of stem cells in HPV-associated carcinogenesis.

HPV - HPV infection - carcinogenesis - cervical cancer - stem cells