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Molecular events associated with dysplastic morphologic transformation and initiation of ovarian tumorigenicity
Dong-Hua Yang1, Elizabeth R Smith, Cynthia Cohen
1Ovarian Cancer Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA.
Background:
Disabled-2 (Dab2), a candidate tumor suppressor of ovarian carcinoma, frequently (around 80%) loses its expression in ovarian tumors. Expression of exogenous Dab2 in tumor cell lines negatively regulates growth and suppresses the downstream signal of the Ras/mitogen activated protein kinase mitogenic pathway. The inactivation of Dab2 is believed to be an early event in ovarian tumorigenicity.
Methods:
The authors analyzed the correlation among expression of Dab2, presence of basement membrane (collagen IV and laminin), morphologic alteration of the surface epithelial cells, and expression of the mitotic index marker Mib-1 in 50 archived ovarian tumors by an immunohistochemical approach. The stainings of Dab2, Mib-1, collagen IV, and laminin in premalignant lesions bordering both normal and neoplastic ovarian surface epithelium from adjacent slides were analyzed in 50 ovarian tumors.
Results:
In these 50 ovarian tumors, the percentage of Mib-1 positive tumor cells distributed in a wide range, from 1% to 75%, and there has no strong correlation with the expression of Dab2. However, in the premalignant regions bordering tumor and normal ovarian surface epithelium, the loss of Dab2 expression closely correlated with the dysplastic morphologic transition and Mib-1 expression of the ovarian surface epithelial cells. In 20 foci in 12 out of the 50 tumors, a transition from normal to neoplastic morphology within a contiguous epithelium was observed, and in all cases the morphologic change correlated with the loss of Dab2 staining. In addition, the collagen and laminin staining of the basement membrane were absent or weakened in pre-malignant epithelium prior to loss of Dab2 expression in all these 20 cases. Nevertheless, collagen IV and laminin were detectable in established adenomas on the same tumor slides.
Conclusions:
The loss of Dab2 is closely associated with the transition of ovarian surface epithelial cells to premalignant states and is likely involved in the initiation of ovarian tumorigenicity. Transient loss of collagen IV and laminin in the basement membrane of the premalignant epithelium and subsequent inactivation of Dab2 are common early events associated with tumorigenicity of the ovarian surface epithelium.
Insights
Loss of Disabled-2 (Dab2) expression correlates with early ovarian cancer development. This loss precedes basement membrane changes and is linked to premalignant cell transitions, suggesting its role in ovarian tumorigenesis.
Area of Science:
- Oncology
- Cell Biology
- Biochemistry
Background:
- Disabled-2 (Dab2) is a candidate tumor suppressor in ovarian carcinoma, with expression lost in approximately 80% of ovarian tumors.
- Exogenous Dab2 expression inhibits tumor cell growth and the Ras/MAPK signaling pathway.
- Dab2 inactivation is considered an early event in ovarian tumorigenesis.
Purpose of the Study:
- To investigate the correlation between Dab2 expression, basement membrane integrity (collagen IV, laminin), epithelial cell morphology, and Mib-1 expression in ovarian tumors.
- To analyze these factors in premalignant lesions adjacent to normal and neoplastic ovarian surface epithelium.
Main Methods:
- Immunohistochemical analysis of 50 archived ovarian tumors.
- Assessment of Dab2, Mib-1, collagen IV, and laminin expression.
- Examination of premalignant lesions on adjacent tissue slides.
Main Results:
- No strong correlation between Dab2 expression and Mib-1 in established tumors.
- Loss of Dab2 expression strongly correlated with dysplastic morphology and Mib-1 expression in premalignant regions.
- Basement membrane abnormalities (loss/weakening of collagen IV and laminin) preceded Dab2 loss in premalignant epithelium.
Conclusions:
- Loss of Dab2 is associated with the transition to premalignant states and likely initiates ovarian tumorigenicity.
- Transient basement membrane changes and subsequent Dab2 inactivation are early events in ovarian surface epithelium tumorigenesis.