Loss of surface and cyst epithelial basement membranes and preneoplastic morphologic changes in prophylactic oophorectomies

Abstract

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. Cancer 2003;98:2607–23. ...

Loss of TNF-α-regulated COX-2 expression in ovarian cancer cells

“…Although increased COX-2 expression was often observed in preneoplastic ovarian surface epithelium (Roland et al, 2003), the direct stimulator of COX-2 expression was not yet established. Reproductive hormones and local mediators of ovulation are likely candidates to regulate COX-2 expression.…”

“…In contrast to cancers of other organ sites, ovarian tumors and most ovarian cancer cell lines are negative for COX-2 expression (Gupta et al, 2003;Roland et al, 2003). We analysed the expression of COX-2 and its regulation in five ovarian cancer cell lines: A2780, OVCAR4, OVCAR8, and OVCAR10 are COX-2 negative, and OVCAR5 is positive for COX-2.…”

“…We analysed the expression of COX-2 and its regulation in five ovarian cancer cell lines: A2780, OVCAR4, OVCAR8, and OVCAR10 are COX-2 negative, and OVCAR5 is positive for COX-2. This panel of cancer cell lines represents the frequency of COX-2 expression in ovarian tumors, which are mostly negative and are positive only in less than 10% of the tumors analysed (Roland et al, 2003). , and OVCAR5 were treated with TNF-a (10 ng/ml) for 6 h. Cells were harvested to analyse COX-1 and COX-2 protein expression by Western blot.…”

“…Several studies reported the expression of COX-2 in ovarian tumors based on immunostaining (Dore et al, 1998;Klimp et al, 2001;Matsumoto et al, 2001;Denkert et al, 2002;Ferrandina et al, 2002;Shigemasa et al, 2003); however, recent studies suggested that COX-2 is not frequently expressed in ovarian cancer (Gupta et al, 2003;Roland et al, 2003). We found that COX-2 is often expressed in preneoplastic lesions and normal ovarian surface and inclusion cyst epithelia, but it is not normally detected in established ovarian cancer (Roland et al, 2003). It was proposed that COX-2 expression may promote ovarian preneoplastic transformation and underlie the link between the etiological factor of ovulation and ovarian cancer risk (Smith et al, 2004).…”

Activation of BTAK expression in primary ovarian surface epithelial cells of prophylactic ovaries

“…While several studies have failed to detect such difference at the histopathological level, 11,[27][28][29][30] others have detected such differences between these two different groups. 10,12,[31][32][33][34][35][36][37] In addition, human ovarian-surface epithelial (HOSE) cells from patients with a family history of breast or ovarian cancer show increased CA-125 expression 34 and more stable expression of the Met receptor for hepatocyte growth factor (HGF) than do HOSE cells from patients without such a history. 38 Transformation of HOSE cells with the SV40 T/t antigen led to increased telomere instability and reduced growth potential in cells from patients with a family history of breast or ovarian cancer, indicating that those cells were closed to replicative senescence.…”