Article (Scientific journals)
Through the glass darkly: intraepithelial neoplasia, top-down differentiation and the road to ovarian cancer.
Crum, Christopher P.; Herfs, Michael; Ning, Gang et al.
2013In Journal of Pathology, 231, p. 402-412
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Keywords :
BRCA; Ovarian cancer; Serous cancer; Stem cell; fallopian tube; p53; p53 signature
Abstract :
[en] It is currently hoped that deaths from extra-uterine high-grade serous cancer (HGSC) will be reduced via opportunistic salpingectomy in healthy women. Accumulated data implicate the fimbria as a site of origin and descriptive molecular pathology and experimental evidence strongly support a serous carcinogenic sequence in the fallopian tube. Both direct and indirect ("surrogate") precursors suggest the benign tube undergoes important biologic changes after menopause, acquiring abnormalities in gene expression that are often shared with malignancy, including PAX2, ALDH1, LEF1, RCN1, RUNX2, beta catenin, EZH2 and others. However, the tube can be linked to only some HGSCs, recharging arguments that nearby peritoneum/ovarian surface epithelium (POSE) also hosts progenitors to this malignancy. A major sticking point is the difference in immunophenotype between POSE and Mullerian epithelium, essentially requiring mesothelial to Mullerian differentiation prior to or during malignant transformation to HGSC. However, emerging evidence implicates an embryonic or progenitor phenotype in the adult female genital tract with the capacity to differentiate, normally or during neoplastic transformation. Recently, a putative cell of origin to cervical cancer has been identified in the squamo-columnar (SC) junction, projecting a model whereby Krt7+ embryonic progenitors give rise to immuno-phenotypically distinct progeny under stromal influences via "top down" differentiation. Similarly, biphasic cell differentiation can be seen in the endometrium with a parallel in the juxtaposition of mesothelial and mullerian differentiation in the ovary. An abrupt mesothelial-Mullerian transition remains to be proven, but would explain the rapid evolution, short asymptomatic interval, and absence of a defined epithelial starting point in many HGSCs. Resolving this question will require accurately distinguishing progenitor from progeny tumor cells in HGSC and pinpointing where initial transformation and trans-differentiation occurs if the POSE is an origin. Both will be critical to expectations from prophylactic salpingectomy and future approaches to pelvic serous cancer prevention.
Disciplines :
Oncology
Author, co-author :
Crum, Christopher P. 
Herfs, Michael  ;  Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Anatomie et cytologie pathologiques
Ning, Gang 
Bijron, Jonathan G.
Howitt, Brooke E.
Jimenez, Cynthia A.
Hanamornroongruang, Suchanan
McKeon, Frank D.
Xian, Wa
 These authors have contributed equally to this work.
Language :
English
Title :
Through the glass darkly: intraepithelial neoplasia, top-down differentiation and the road to ovarian cancer.
Publication date :
2013
Journal title :
Journal of Pathology
ISSN :
0022-3417
eISSN :
1096-9896
Publisher :
John Wiley & Sons, Chichester, United Kingdom
Volume :
231
Pages :
402-412
Peer reviewed :
Peer Reviewed verified by ORBi
Commentary :
This article is protected by copyright. All rights reserved.
Available on ORBi :
since 09 January 2014

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