[en] The oviducts contain high-grade serous cancer (HGSC) precursors (serous tubal intraepithelial neoplasia or STINs), which are gamma-H2AXp - and TP53 mutation-positive. Although they express wild-type p53, secretory cell outgrowths (SCOUTs) are associated with older age and serous cancer; moreover, both STINs and SCOUTs share a loss of PAX2 expression (PAX2n ). We evaluated PAX2 expression in proliferating adult and embryonic oviductal cells, normal mucosa, SCOUTs, Walthard cell nests (WCNs), STINs, and HGSCs, and the expression of genes chosen empirically or from SCOUT expression arrays. Clones generated in vitro from embryonic gynaecological tract and adult Fallopian tube were Krt7p /PAX2n /EZH2p and underwent ciliated (PAX2n /EZH2n /FOXJ1p ) and basal (Krt7n /EZH2n /Krt5p ) differentiation. Similarly, non-ciliated cells in normal mucosa were PAX2p but became PAX2n in multi-layered epithelium undergoing ciliated or basal (WCN) cell differentiation. PAX2n SCOUTs fell into two groups: type 1 were secretory or secretory/ciliated with a 'tubal' phenotype and were ALDH1n and beta-cateninmem (membraneous only). Type 2 displayed a columnar to pseudostratified (endometrioid) phenotype, with an EZH2p , ALDH1p , beta-cateninnc (nuclear and cytoplasmic), stathminp , LEF1p , RCN1p , and RUNX2p expression signature. STINs and HGSCs shared the type 1 immunophenotype of PAX2n , ALDH1n , beta-cateninmem , but highly expressed EZH2p , LEF1p , RCN1p , and stathminp . This study, for the first time, links PAX2n with proliferating fetal and adult oviductal cells undergoing basal and ciliated differentiation and shows that this expression state is maintained in SCOUTs, STINs, and HGSCs. All three entities can demonstrate a consistent perturbation of genes involved in potential tumour suppressor gene silencing (EZH2), transcriptional regulation (LEF1), regulation of differentiation (RUNX2), calcium binding (RCN1), and oncogenesis (stathmin). This shared expression signature between benign and neoplastic entities links normal progenitor cell expansion to abnormal and neoplastic outgrowth in the oviduct and exposes a common pathway that could be a target for early prevention. Copyright (c) 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Disciplines :
Oncology
Author, co-author :
Ning, Gang
Bijron, Jonathan G.
Yamamoto, Yusuke
Wang, Xia
Howitt, Brooke E.
Herfs, Michael ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Anatomie et cytologie pathologiques
Piek JM, van Diest PJ, Zweemer RP, et al. Dysplastic changes in prophylactically removed Fallopian tubes of women predisposed to developing ovarian cancer. J Pathol 2001; 195: 451-456.
Kindelberger DW, Lee Y, Miron A, et al. Intraepithelial carcinoma of the fimbria and pelvic serous carcinoma: evidence for a causal relationship. Am J Surg Pathol 2007; 31: 161-169.
Finch A, Shaw P, Rosen B, et al. Clinical and pathologic findings of prophylactic salpingo-oophorectomies in 159 BRCA1 and BRCA2 carriers. Gynecol Oncol 2006; 100: 58-64.
Lee Y, Miron A, Drapkin R, et al. A candidate precursor to serous carcinoma that originates in the distal Fallopian tube. J Pathol 2007;211:26-35. Erratum in J Pathol 2007; 213: 116.
Crum CP, Herfs M, Ning G, et al. Through the glass darkly: intraepithelial neoplasia, top-down differentiation and the road to ovarian cancer. J Pathol 2013; 231: 402-412.
Carlson JW, Miron A, Jarboe EA, et al. Serous tubal intraepithelial carcinoma: its potential role in primary peritoneal serous carcinoma and serous cancer prevention. J Clin Oncol 2008; 26: 4160-4165.
Chen EY, Mehra K, Mehrad M, et al. Secretory cell outgrowth, PAX2 and serous carcinogenesis in the Fallopian tube. J Pathol 2010; 222: 110-116.
Quick CM, Ning G, Bijron J, et al. PAX2-null secretory cell outgrowths in the oviduct and their relationship to pelvic serous cancer. Mod Pathol 2012; 25: 449-455.
Bijron JG, Ning G, Laury AR, et al. Digital quantification of precursor frequency in the Fallopian tube and its significance. Mod Pathol 2012; 25: 1654-1661.
Mehrad M, Ning G, Chen EY, et al. A pathologist's road map to benign, precancerous, and malignant intraepithelial proliferations in the Fallopian tube. Adv Anat Pathol 2010; 17: 293-302.
Kumar PA, Hu Y, Yamamoto Y, et al. Distal airway stem cells yield alveoli in vitro and during lung regeneration following H1N1 influenza infection. Cell 2011; 147: 525-538.
Laury AR, Ning G, Quick CM, et al. Fallopian tube correlates of ovarian serous borderline tumors. Am J Surg Pathol 2011; 35: 1759-1765.
Vang R, Visvanathan K, Gross A, et al. Validation of an algorithm for the diagnosis of serous tubal intraepithelial carcinoma. Int J Gynecol Pathol 2012; 31: 243-253.
Ning G, Bijron JG, Yuan J, et al. Differential expression of p-ERM, a marker of cell polarity, in benign and neoplastic oviductal epithelium. Int J Gynecol Pathol 2013; 32: 345-352.
Lee S, Nelson G, Duan Q, et al. Precursor lesions and prognostic factors in primary peritoneal serous carcinoma. Int J Gynecol Pathol 2013; 32: 547-555.
Wethington SL, Park KJ, Soslow RA, et al. Clinical outcome of isolated serous tubal intraepithelial carcinomas (STIC). Int J Gynecol Cancer 2013; 23: 1603-1611.
Lowell CB, Swisher EM, Cass I, et al. Long term followup of BRCA1 and BRCA2 mutation carriers with unsuspected neoplasia identified at risk reducing salpingo-oophorectomy. Gynecol Oncol 2013; 129: 364-371.
Conner JR, Meserve E, Pizer E, et al. Outcome of unexpected adnexal neoplasia discovered during risk reduction salpingo-oophorectomy in women with germ-line BRCA1 or BRCA2 mutations. Gynecol Oncol 2014; 132: 280-286.
Seidman JD, Yemelyanova A, Zaino RJ, et al. The Fallopian tube-peritoneal junction: a potential site of carcinogenesis. Int J Gynecol Pathol 2011; 30: 4-11.
Wang X, Ouyang H, Yamamoto Y, et al. Residual embryonic cells as precursors of a Barrett's-like metaplasia. Cell 2011; 145: 1023-1035.
Herfs M, Yamamoto Y, Laury A, et al. A discrete population of squamocolumnar junction cells implicated in the pathogenesis of cervical cancer. Proc Natl Acad Sci U S A 2012; 109: 10516-10521.
Sehdev AS, Kurman RJ, Kuhn E, et al. Serous tubal intraepithelial carcinoma upregulates markers associated with high-grade serous carcinomas including Rsf-1 (HBXAP), cyclin E and fatty acid synthase. Mod Pathol 2010; 23: 844-855.
Marquez RT, Baggerly KA, Patterson AP, et al. Patterns of gene expression in different histotypes of epithelial ovarian cancer correlate with those in normal Fallopian tube, endometrium, and colon. Clin Cancer Res 2005; 11: 6116-6126.
Levanon K, Ng V, Piao HY, et al. Primary ex vivo cultures of human Fallopian tube epithelium as a model for serous ovarian carcinogenesis. Oncogene 2010; 29: 1103-1113.
Deng S, Yang X, Lassus H, et al. Distinct expression levels and patterns of stem cell marker, aldehyde dehydrogenase isoform 1 (ALDH1), in human epithelial cancers. PLoS One 2010; 5: e10277.
Flesken-Nikitin A, Hwang CI, Cheng CY, et al. Ovarian surface epithelium at the junction area contains a cancer-prone stem cell niche. Nature 2013; 495: 241-245.
Chou RH, Yu YL, Hung MC. The roles of EZH2 in cell lineage commitment. Am J Transl Res 2011; 3: 243-250.
Deb G, Singh AK, Gupta S. EZH2: not EZHY (easy) to deal. Mol Cancer Res 2014; 12: 639-653.
Merrill BJ, Gat U, DasGupta R, et al. Tcf3 and Lef1 regulate lineage differentiation of multipotent stem cells in skin. Genes Dev 2001; 15: 1688-1705.
Giribaldi G, Barbero G, Mandili G, et al. Proteomic identification of Reticulocalbin 1 as potential tumor marker in renal cell carcinoma. J Proteomics 2013; 91: 385-392.
Yoshida T, Kanegane H, Osato M, et al. Functional analysis of RUNX2 mutations in Japanese patients with cleidocranial dysplasia demonstrates novel genotype-phenotype correlations. Am J Hum Genet 2002; 71: 724-738.
Karst AM, Levanon K, Duraisamy S, et al. Stathmin 1, a marker of PI3K pathway activation and regulator of microtubule dynamics, is expressed in early pelvic serous carcinomas. Gynecol Oncol 2011; 123: 5-12.
Zheng P, Liu YX, Chen L, et al. Stathmin, a new target of PRL-3 identified by proteomic methods, plays a key role in progression and metastasis of colorectal cancer. J Proteome Res 2010; 9: 4897-4905.
Sonego M, Schiappacassi M, Lovisa S, et al. Stathmin regulates mutant p53 stability and transcriptional activity in ovarian cancer. EMBO Mol Med 2014; 6: 295.
Hueber PA, Waters P, Clark P, et al. PAX2 inactivation enhances cisplatin-induced apoptosis in renal carcinoma cells. Kidney Int 2006; 69: 1139-1145.
Han X, Du F, Jiang L, et al. A2780 human ovarian cancer cells with acquired paclitaxel resistance display cancer stem cell properties. Oncol Lett 2013; 6: 1295-1298.
Rizzo S, Hersey JM, Mellor P, et al. Ovarian cancer stem cell-like side populations are enriched following chemotherapy and overexpress EZH2. Mol Cancer Ther 2011; 10: 325-335.
van der Zee M, Jia Y, Wang Y, et al. Alterations in Wnt-β-catenin and Pten signalling play distinct roles in endometrial cancer initiation and progression. J Pathol 2013; 230: 48-58.