Abstract 3348: Expression of putative cancer stem cell markers in fallopian tube epithelium from women at increased risk of developing high-grade serous ovarian cancer

Abstract

Abstract Pre-neoplastic p53 signature containing lesions, termed serous tubal intraepithelial carcinomas (STICs), have been identified in the fimbriae of women predisposed to ovarian cancer and in patients with sporadic high grade serous ovarian cancer (HGSOC). These findings instigated the theory that HGSOC originates from fallopian tube epithelium (FTE) and not from ovarian surface epithelium (OSE), and has now become an accepted paradigm for HGSOC genesis. However, only few studies have investigated the stem cell niche in the human fallopian tube. Instead, most research on ovarian cancer stem cells has focused on cells isolated from primary ovarian tumors or cell lines. In this study we performed immunohistochemistry to explore the presence of putative ovarian cancer stem cells in fallopian tubes from women who had undergone a risk reducing salpingo-oophorectomy (RRSO) due to a germline BRCA1/2 mutation and/or strong family history. Sections of frozen tissue from 14 RRSO patients (10 BRCA1/2 mutation carriers, 4 tested negative for BRCA1/2 mutations) were used in immunohistochemistry for p53 and the proposed cancer stem cell markers ALDH1, CD44, CD117, CD133, LGR5 and SOX2. Presence of a p53 signature (>12 consecutive cell nuclei in normal appearing FTE) was observed in 1 of 10 BRCA1/2 mutation carriers and none of the non-carriers. ALDH1 and CD44 positive staining of varying intensity was found in both FTE cells and stromal cells within the fallopian tube mucosa in all cases. On the other hand, no CD117 positive epithelial cells were observed in any of the samples, though strongly stained CD117+ mast cells were present in all sections. Most FTE cells were weakly positive for CD133 in all sections, while only one case showed positive LGR5 staining of FTE cells. Finally, SOX2 positive FTE cells were found in all samples. In most cases, the fimbriated end of the fallopian tube harbored more SOX2 positive cells than the more proximal end. This is an initial attempt at visualizing proposed ovarian cancer stem cells in the fallopian tubes of women predisposed to developing HGSOC. Further research is needed to validate the significance of these findings, including investigating additional markers, testing different antibodies and performing multiple labeling experiments. Based on the currently prevailing theory that HGSOC originates from STICs in the fimbriated end of the fallopian tube, we find SOX2 to be the most promising candidate for further investigations, since SOX2 was the only marker found to be differentially expressed throughout the fallopian tube. Elucidating the cell of origin and etiology of HGSOC has important implications for early detection and preventive therapeutic approaches. Citation Format: Anna Ebbesson, Susanne Malander, Päivi Kannisto, Anita Ringberg, Anna Måsbäck, Ingrid A. Hedenfalk. Expression of putative cancer stem cell markers in fallopian tube epithelium from women at increased risk of developing high-grade serous ovarian cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3348.