The DNA Damage Response of Fallopian Tube Secretory Epithelial Cells Renders Them Susceptible to Carcinogenesis
K Levanon, V Ng, MC Chang, PD Vermeer, JL Zabner, CP Crum, RI Drapkin. Dana-Farber Cancer Institute, Boston, MA; Brigham and Women's Hospital, Boston, MA; University of Iowa, Iowa City, IA
Background: A growing body of data point to the fallopian tube secretory epithelial cells (FTSECs) as the cell-of-origin of most of both hereditary and sporadic cases of serous pelvic carcinoma. The fallopian tube is lined with epithelium that is composed of two cell lineages: FTSECs and ciliated cells. We hypothesized that the FTSEC is susceptible to DNA damaging effects associated with ovulation and that repeated and prolonged genotoxic stress leads to the development of carcinoma through a multi-step process. Investigating the mechanisms underlying the increased susceptibility of FTSECs to DNA damage, relative to the ciliated cells required the development of unique in vitro tools for co-culturing the two sub-populations of cells from human tissue samples.
Design: We co-cultured primary human FT epithelial cells, including both FTSECs and ciliated cells, under unique conditions which preserve the specific differentiation markers ('ex vivo culture system'). We exposed the co-cultures to different modalities of low dose DNA damage, including ionizing radiation, chemotherapeutic drugs, and oxidative damage, and analyzed the response.
Results: The ex vivo co-culture system of primary human FT epitheial cells proved to be a reproducible phenocopy of the in vivo endosalpynx. FTSECs displayed a unique DNA damage response compared to the neighboring ciliated cells. It is characterized by accelerated activation of the cellular repair machinery along with ineffective resolution of DNA lesions over an extensive period of time. A similar pattern is seen in situ when DNA damage is induced in whole human FT fimbria specimens.
Conclusions: This study, for the first time, confirms that FTSECs are a unique population of epithelial cells with a distinctly different response to genotoxic stress relative to ciliated cells in vitro. This finding is in parallel with the observations in vivo that DNA damage and TP53 mutations are specific for this cell type. Damaged FTSECs may persist in the endosalpynx under replication checkpoints, however repeated insults, induced by ovulation or other endogenous or exogenous factors, may eventually lead to acquisition of enough mutations to allow escape from the cell cycle arrest, resulting in malignant transformation.
Tuesday, March 10, 2009 1:00 PM
Poster Session IV # 173, Tuesday Afternoon