Early alterations in ovarian surface epithelial cells and induction of ovarian epithelial tumors triggered by loss of FSH receptor.
Little is known about the behavior of the ovarian surface epithelium (OSE), which plays a central role in ovarian cancer etiology. It has been suggested that incessant ovulation causes OSE changes leading to transformation and that high gonadotropin levels during postmenopause activate OSE receptors, inducing proliferation. We examined the chronology of OSE changes, including tumor appearance, in a mouse model where ovulation never occurs due to deletion of follitropin receptor. Changes in epithelial cells were marked by pan-cytokeratin (CK) staining. Histologic changes and CK staining in the OSE increased from postnatal day 2. CK staining was observed inside the ovary by 24 days and increased thereafter in tumor-bearing animals. Ovaries from a third of aged (1 year) mutant mice showed CK deep inside, indicating cell migration. These tumors resembled serous papillary adenoma of human ovaries. Weak expression of GATA-4 and elevation of PCNA, cyclooxygenase-1, cyclooxygenase-2, and platelet-derived growth factor receptors alpha and beta in mutants indicated differences in cell proliferation, differentiation, and inflammation. Thus, we report that OSE changes occur long before epithelial tumors appear in FORKO mice. Our results suggest that neither incessant ovulation nor follicle-stimulating hormone receptor presence in the OSE is required for inducing ovarian tumors; thus, other mechanisms must contribute to ovarian tumorigenesis.
Chen
Xinlei
X
Molecular Reproduction Research Laboratory, Clinical Research Institute of Montreal, Univerisité de Montréal, Montreal, Quebec H2W 1R7, Canada.
Aravindakshan
Jayaprakash
J
Yang
Yinzhi
Y
Sairam
M Ram
MR
D000236:Adenoma / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D018293:Cystadenoma, Serous / Q000378:metabolism* / Q000473:pathology; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D005260:Female; D005455:Fluorescent Antibody Technique; D050991:GATA4 Transcription Factor / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D007249:Inflammation; D007633:Keratins / Q000378:metabolism; D051379:Mice; D010051:Ovarian Neoplasms / Q000378:metabolism* / Q000473:pathology; D010053:Ovary / Q000378:metabolism* / Q000473:pathology; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D011962:Receptors, FSH / Q000378:metabolism*; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism
D050991:GATA4 Transcription Factor; D018809:Proliferating Cell Nuclear Antigen; D011962:Receptors, FSH; D007633:Keratins; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D017479:Receptors, Platelet-Derived Growth Factor