Novel Model Systems To Study the Fallopian Tube Secretory Epithelium The Cell-of-Origin of Serous Pelvic Carcinoma
K Levanon, AK Folkins, RI Drapkin. Dana-Farber Cancer Institute, Boston, MA; Brigham and Women's Hospital, Boston, MA
Background: Serous carcinoma is the most aggressive sub-type of endothelial ovarian carcinoma. It has been traditionally attributed to the ovarian surface epithelium (OSE), or surface-derived intracortical Mullerian inclusions as the fields of origin. Recent studies suggest that the fallopian tube (FT) fimbria, rather than the OSE, may be the site of origin for over 50% of sporadic and hereditary serous carcinomas, with secondary involvement of the ovaries and peritoneum. An early precursor lesion, the 'p53 signature', characterized by DNA damage, TP53 gene mutations and p53 protein accumulation has been described in normal-appearing secretory epithelial cells (FTSEC). With the emergence of the FTSEC as a putative cell-of-origin for high grade serous carcinomas, the development of in vitro and in vivo model systems is warranted to help propel further discovery.
Design: To address the series of events that culminates in transformation of the secretory cells, we isolated pure primary FTSECs and immortalize them in culture by overexpressing hTERT. Furthermore, we transformed several FTSEC lines by serial introduction of oncogenes, as previously described in other epithelial cell types, and established a xenograft model in mice.
Results: The immortalized FTSECs cell lines could be propagated for over 10 passages and be genetically manipulated. The transformed FTSECs acquired an aggressive morphology and an anchorage-independent growth capability in vitro, and, more importantly, formed tumors in immunodeficient mice.
Conclusions: FTSECs are a unique population of epithelial cells with an increased susceptibility to malignant transformation, as judged by its exclusive involvement in serous carcinoma. The FTSECs cell lines are an invaluable tool for the studying the effects of clinically-relevant defined genetic alterations (such as TP53 and BRCA1 and 2 mutations or the activation of the c-myc and PI3K/Akt pathways) both in vitro and in vivo. The artificially transformed FTSECs are the first of its kind proof-of-concept of the tumorigenic capacity of this cell lineage. These novel model systems, which will be illustrated, are essential for basic and translational research aimed at deciphering the underlying mechanism of serous carcinogenesis and developing targeted therapeutics and biomarkers for serous pelvic carcinoma.
Tuesday, March 10, 2009 1:00 PM
Poster Session IV # 172, Tuesday Afternoon