Background: A spectrum of precursors has been identified in the distal fallopian tube with a relationship to pelvic serous cancer ("ovarian cancer") and linked to p53 mutations, absence of PAX2 expression (PAX2-) or both. Because a wide range of precursors are PAX2-, we hypothesized that the PAX2- immunophenotype was a property of a serous cancer progenitor cell rather than acquired during neoplastic transformation. This study explored this concept.
Methods: Oviductal epithelia were immunostained concurrently with PAX2 (a non-ciliated cell marker), FOXJ1 (a ciliated cell marker) and CD3 (lymphocyte marker) to identify PAX2- secretory cells. Genes over-expressed in PAX2- precursors based on expression arrays were selected (ALDH1, LEF1, EZH2). Derived antibodies were used to co-localize expression with the PAX2- cells candidate progenitor cells, precursor lesions and serous carcinomas.
Results: Immunostaining of human and murine oviducts revealed discrete PAX2- cells in the epithelium. In the mouse, PAX2- cells were confined to the distal tube. PAX2- cells were seen individually and in non-stratified epithelium and accounted for less than 10% of the non-ciliated cell population. However, PAX2- cell clusters were discovered and larger populations of PAX2- cells were identified, both in the middle of the epithelium and adjacent to the basement membrane. Discrete expansions (termed secretory cell outgrowths or SCOUTs) were common, particularly in fallopian tubes of women with pelvic serous cancer, and coincided with an ALDH1-, LEF1+, EZH2+ immunophenotype. This same immunophenotype characterized serous cancer precursors associated with over-accumulation of p53 (p53 signatures, serous tubal intraepithelial carcinomas) and invasive serous carcinomas.
Conclusion: This report proposes a candidate cell of origin for both benign proliferations and high grade serous carcinoma in the oviduct that is a PAX2- secretory cell. The distribution of the PAX2- cells is emblematic of their role in both physiologic cell proliferation and clonal expansion, the latter including altered expression of ALDH1, LEF1 and EZH2, among others. The phenotypic range of PAX2- cell expansions is consistent with the imposition of multiple stimuli on this cell, including both preservation and loss of p53 function. This population of PAX2- cells provides a unique substrate for studying cell-specific vulnerabilties in serous carcinogenesis and the molecular underpinnings of the varied differentiation paths that seem to ensue during clonal expansion of this unique cell type.
Citation Format: Gang Ning, Michael Herfs, Jonathan G. Bijron, Yasuke Yamamoto, Daniela Dinulescu, Frank D. McKeon, Christopher P. Crum, Wa Xian. Serous cancer progenitor cells in the oviduct. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4791. doi:10.1158/1538-7445.AM2013-4791