Loss of surface and cyst epithelial basement membranes and preneoplastic morphologic changes in prophylactic oophorectomies.
BACKGROUND
The authors suggested that the loss of collagen IV and laminin-containing basement membrane and the loss of Disabled-2 (Dab2) expression were two critical events associated with morphologic dysplastic changes of the ovarian surface epithelium as a step in tumorigenicity. Both the basement membrane and Dab2, a candidate tumor suppressor of ovarian carcinoma, were involved in epithelial cell surface positioning and organization. The authors speculated that the purging of the basement membrane may be similar to the proteolysis during gonadotropin-stimulated ovulation, a cyclooxygenase 2 (Cox-2)-mediated process.


METHODS
Prophylactic oophorectomy is used to prevent breast and ovarian carcinoma in high-risk populations. These ovarian tissue specimens often contain an increased presence of morphologically abnormal lesions that are believed to be preneoplastic. The authors evaluated archived prophylactic oophorectomy specimens to verify whether the loss of Dab2 expression and the removal of the basement membrane that occur at the ovarian surface and inclusion cyst epithelia are molecular markers of preneoplastic lesions. Of the 36 samples containing identifiable ovarian surface epithelial components on slides, immunostaining was employed to evaluate the intactness of the basement membrane (periodic acid-Schiff [PAS], collagen IV, and laminin) and the expression of Dab2 and Cox-2. Expression of Cox-1 and Cox-2 also were evaluated in cultured ovarian surface epithelial cells prepared from ovarian tissue specimens removed from patients who underwent prophylactic surgery.


RESULTS
The morphologically normal ovarian surface epithelium typically contained a collagen IV- and laminin-positive basement membrane, which also was detected by PAS staining. Many morphologically altered areas, such as papillomatosis, invaginations, inclusion cysts, stratification, adenomas, and microscopic adenocarcinomas, were found in these specimens. Both the morphologically altered and adjacent morphologically normal epithelia consistently exhibited loss of basement membrane and/or Dab2 expression and an increase in Cox-2 staining. Frequently, an increase in Cox-2 staining was correlated with the loss of epithelial basement membrane in morphologically normal areas.


CONCLUSIONS
The loss of Dab2 and basement membrane and the overexpression of Cox-2 were observed in presumptive neoplastic precursor areas of oophorectomy specimens obtained from a population at high risk for ovarian carcinoma. Transient loss of collagen IV and laminin in the basement membrane of the preneoplastic epithelium and the loss of Dab2 expression are common early events associated with morphologic alteration and tumorigenicity of the ovarian surface epithelium. The authors concluded that Cox-2 overexpression may play a role in the purging of basement membrane of the ovarian surface epithelium, mimicking the process of ovulation. Further experiments may be able to test the hypothetical model derived from these histologic observations.
Roland
Isabelle H
IH
Ovarian Cancer Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA.
Yang
Wan-Lin
WL
Yang
Dong-Hua
DH
Daly
Mary B
MB
Ozols
Robert F
RF
Hamilton
Thomas C
TC
Lynch
Henry T
HT
Godwin
Andrew K
AK
Xu
Xiang-Xi
XX
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism*; D000328:Adult; D000368:Aged; D051017:Apoptosis Regulatory Proteins; D001485:Basement Membrane / Q000378:metabolism / Q000473:pathology; D002471:Cell Transformation, Neoplastic; D024141:Collagen Type IV / Q000032:analysis / Q000096:biosynthesis; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D004847:Epithelial Cells / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006801:Humans; D007124:Immunoenzyme Techniques; D007527:Isoenzymes / Q000378:metabolism*; D019394:Ki-67 Antigen / Q000032:analysis; D007797:Laminin / Q000032:analysis / Q000096:biosynthesis; D008565:Membrane Proteins; D008875:Middle Aged; D010048:Ovarian Cysts / Q000378:metabolism / Q000473:pathology*; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000601:surgery; D010052:Ovariectomy; D010053:Ovary / Q000473:pathology; D011230:Precancerous Conditions / Q000473:pathology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D025521:Tumor Suppressor Proteins
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D051017:Apoptosis Regulatory Proteins; D024141:Collagen Type IV; C102885:DAB2 protein, human; D007527:Isoenzymes; D019394:Ki-67 Antigen; D007797:Laminin; D008565:Membrane Proteins; D025521:Tumor Suppressor Proteins; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases