LEF1 is preferentially expressed in the tubal-peritoneal junctions and is a reliable marker of tubal intraepithelial lesions

Abstract

Recently it has been reported that serous tubal intraepithelial carcinoma (STIC), the likely precursor of ovarian/extra-uterine high-grade serous carcinoma, are frequently located in the vicinity of tubal-peritoneal junctions, consistent with the cancer-prone features of many epithelial transitional regions. To test if p53 (aka TP53)-signatures and secretory cell outgrowths (SCOUTs) also localize to tubal-peritoneal junctions, we examined these lesions in the fallopian tubes of patients undergoing salpingo-oophorectomy for sporadic high-grade serous carcinomas or as a prophylactic procedure for carriers of familial BRCA1 or 2 mutations. STICs were located closest to the tubal-peritoneal junctions with an average distance of 1.31 mm, while SCOUTs were not detected in the fimbriated end of the fallopian tube. Since many epithelial transitional regions contain stem cells, we also determined the expression of stem cell markers in the normal fallopian tube, tubal intraepithelial lesions and high-grade serous carcinomas. Of those, LEF1 was consistently expressed in the tubal-peritoneal junctions and all lesions, independent of p53 status. All SCOUTs demonstrated strong nuclear expression of β-catenin consistent with the LEF1 participation in the canonical WNT pathway. However, β-catenin was preferentially located in the cytoplasm of cells comprising STICs and p53 signatures, suggesting WNT-independent function of LEF1 in those lesions. Both frequency of LEF1 expression and β-catenin nuclear expression correlated with the worst 5 year patient survival, supporting important role of both proteins in high-grade serous carcinoma. Taken together, our findings suggest the existence of stem cell niche within the tubal-peritoneal junctions. Furthermore, they support the notion that the pathogenesis of SCOUTs is distinct from that of STICs and p53 signatures. The location and discrete patterns of LEF1 and β-catenin expression may serve as highly sensitive and reliable ancillary markers for the detection and differential diagnosis of tubal intraepithelial lesions.

WNT and inflammatory signaling distinguish human Fallopian tube epithelial cell populations

“…Our bulk organoid formation results therefore strengthen the notion that the distal TE's stem/progenitor cells or their environment differ in some way from those of the proximal region. These findings are consistent with observations that the distal region of the Fallopian tube more frequently contains putative HGSC precursor lesion (Kim et al, 2018;Lee et al, 2007;Schmoeckel et al, 2017).…”

“…Stem cells are frequently implicated in malignant transformation (Flesken-Nikitin et al, 2013;Nassar and Blanpain, 2016), thus regional differences in the TE stem cells may account for the distal TE's tendency to harbor STICs. Indeed, previous studies based on immunohistochemical analysis of TE sections have suggested that stem/progenitor cells may occur more frequently in the distal TE (Paik et al, 2012;Schmoeckel et al, 2017). Support for this notion also comes from the observations of preferential sphere formation by human distal TE (Paik et al, 2012) and organoid formation of the mouse distal oviduct (the mouse analogue to the Fallopian tube (Xie et al, 2018).…”

Ovarian Cancers: Genetic Abnormalities, Tumor Heterogeneity and Progression, Clonal Evolution and Cancer Stem Cells

“…Thus, Latifi and coworkers have shown that cisplatin induces an epithelial to mesenchymal transition in ovarian cancer cells derived from advanced stage patients: tumor cells surviving to cisplatin treatment in vitro changed their morphology from a typical epithelial to a typical mesenchymal pattern, reduced E-cadherin and increased N-cadherin and vimentin expression; in parallel, it was observed an increased expression of stem cell-associated membrane markers such as CD133, CD44, CD117, EpCAM and of the stem cell factors Nanog and Oct-4 [ 248 ]. Recurrent ovarian tumors are enriched with cancer stem cell-like cells and stem cell mediators, such as CD44, CD133, NOTCH, Wnt, TGFbeta, ALDH1, thus supporting the hypothesis that cancer stem cells contribute to the disease recurrence [ 192 ].…”

“…Interestingly, most of STICs are located in proximity of the tubal-peritoneal junction [ 191 ]. At the level of the tubal-peritoneal junction putative stem cells were identified, characterized by the expression of LEF1 (Lymphoid Enhancer-Binding Factor 1, a transcription factor that interacts with β-catenin in the nucleus as a component of WNT signaling), thus further supporting the existence of a stem cell niche within the tubal-peritoneal junctions [ 192 ]. All early dysplastic lesions (p53 signatures, SCOUT (secretory cell outgrowths) and STICs) display discrete patterns of LEF1 and β-catenin expression: particularly, LEF1 expression with strong nuclear location of β-catenin is indicative of SCOUTS, while LEF1 expression with membranous and cytoplasmic β-catenin is indicative of TP53 signatures and STICs [ 192 ].…”

Most commonly mutated genes in High Grade Serous Ovarian Carcinoma are nonessential for ovarian surface epithelial stem cell transformation

“…Seidman and colleagues (2015) recently demonstrated that most STICs occur in close proximity to the tubal-peritoneal junction (Seidman 2015). Other studies have demonstrated that the tubal-peritoneal junction, like the ovarian hilum region, contains LEF1-expressing cells, and that patients with higher LEF1 expression had poorer 5 year survival (Schmoeckel et al 2017). It is possible, therefore, that HGSC lesions arise in either OSE-SC or TE stem cells located in transitional zones.…”