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. As 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 ß-catenin consistent with the LEF1 participation in the canonical WNT pathway. However, ß-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 ß-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 ß-catenin expression may serve as highly sensitive and reliable ancillary markers for the detection and differential diagnosis of tubal intraepithelial lesions.
Subject(s)
Biomarkers, Tumor/analysis , Carcinoma in Situ/chemistry , Fallopian Tube Neoplasms/chemistry , Lymphoid Enhancer-Binding Factor 1/analysis , Neoplastic Stem Cells/chemistry , Adult , Aged , Aged, 80 and over , BRCA1 Protein/genetics , BRCA2 Protein/genetics , Carcinoma in Situ/genetics , Carcinoma in Situ/pathology , Carcinoma in Situ/surgery , Case-Control Studies , Fallopian Tube Neoplasms/genetics , Fallopian Tube Neoplasms/pathology , Fallopian Tube Neoplasms/surgery , Female , Humans , Immunohistochemistry , Kaplan-Meier Estimate , Middle Aged , Mutation , Neoplasm Grading , Neoplastic Stem Cells/pathology , Predictive Value of Tests , Proportional Hazards Models , Reproducibility of Results , Salpingo-oophorectomy , Stem Cell Niche , Time Factors , Treatment Outcome , Tumor Microenvironment , Tumor Suppressor Protein p53/analysis , beta Catenin/analysisABSTRACT
Ovarian cancer is the fifth leading cause of cancer-related deaths among women in the United States. Recent extensive genomic analyses of epithelial ovarian cancer (EOC), particularly the most common and deadly form of high-grade serous ovarian carcinoma, have provided important insights into the repertoire of molecular aberrations that are characteristic for this malignancy. However, interpretation of the discovered aberrations is complicated because the origin and mechanisms of progression of EOC remain uncertain. Here, we summarize current views on the cell of origin of EOC and discuss recent findings of a cancer-prone stem cell niche for ovarian surface epithelium, one of the major likely sources of EOC. We also outline future directions and challenges in studying the role of stem cell niches in EOC pathogenesis.
