According to Vaughan et al
, ovarian cancer is many diseases (7
). In the past few years, on the basis of a series of morphological and molecular genetic studies, a dualistic model has been proposed that categorizes various types of ovarian cancer into two groups, types I and II. The high-grade OSCs, which are the most common and most lethal of all ovarian epithelial neoplasms, may arise in the distal part of the Fallopian tubes (fimbria, secretory-type cells) and are only secondarily deposited on the ovarian surface. They commonly show genetic instability and p53 mutations (8
However, a PubMed search revealed no earlier studies dealing with normal fimbriae of high- and low-grade OSCs and evaluating which characteristics had altered prior to p53 mutation. In this study, we evaluated the expression of 6 proteins in 28 cases of high-grade OSC and in 26 cases of low-grade OSC. In high-grade OSCs, there was a trend toward increased expression of pAKT and COX-2 in fimbriae without involvement of cancer. Higher E-cadherin positivity was observed in fimbriae of low-grade OSCs than in fimbriae of high-grade OSCs. This indicates that the proliferation, cell adhesion and inflammatory microenvironment of the fimbriae of high-grade OSCs without STIC had changed prior to p53 mutation.
An abundance of basic investigative studies has established the pAKT pathway as a major driver of cancerous behavior, inolved in proliferation, dysregulation of the cell cycle, apoptosis, metabolism, protein synthesis, senescence and other aspects of cell function. In addition, pAKT immunohistochemistry may be useful in the diagnosis and characterization of precancerous and intraepithelial lesions (9
). We observed an increased AKT expression in 61% of high-grade OSCs, as compared with 8% of low-grade OSCs by immunohistochemistry.
E-cadherin is an adhesion molecule that may be involved in the metastasis of ovarian cancer (10
). It has been suggested that E-cadherin acts as a tumor suppressor; furthermore, the transfection of tumor cells with E-cadherin cDNA prevents invasive growth (11
). Thus, reduced cytoplasmic positivity of E-cadherin in high-grade OSC in this study is consistent with the poor outcome of patients with this disease. In our study, its expression was higher in the fimbriae of low-grade OSC than those of high-grade OSC. It is therefore possible that transformed fimbrial epithelial cells of high-grade OSC lose adhesion early in their progression and may slough off and migrate to the ovarian surface or directly to the peritoneum, with minimal ovarian deep involvement.
COX-2 overexpression has been reported in most gynecological neoplasms, including breast, cervix, endometrial and epithelial ovarian cancers. COX-2 expression promotes tumor cell proliferation, reduces apoptosis and induces angiogenesis (12
). With regard to the inflammatory process, the cell proliferation rate has a well-known association with prognosis in ovarian carcinoma (13
). The different expression levels of Cox-2 in low- and high-grade OSCs in our study possibly indicates the different inflammatory microenvironments.
The mechanism by which MMP-2 facilitates early adhesion and invasion involves cleavage of multiple extracellular matrix (ECM) proteins into smaller fragments that serve as better attachment sites. In addition, the inhibition of MMP-2, but not MMP-9, has been reported to significantly reduce ovarian cancer metastasis (14
). A previous study detected active MMP-2 enzyme (62 kDa) only in ovarian cancer (66%) and corresponding metastases (93%), but never in benign or low potential malignancy tumors (15
). We found that the expression level of MMP-2 was similar between the fimbriae of low- and high-grade OSCs, suggesting that the invasiveness of the fimbrial epithelial cells had not emerged.
VEGF expression in ovarian cancer has been evaluated in several studies. In early stage ovarian cancers, increased VEGF expression has been shown to correlate with worse disease-free survival (DFS) and poor overall survival (OS) (16
). In addition, a higher serum level of VEGF associated with ovarian cancer have been considered as an independent risk factor and a prognostic parameter for ascites, more metastasis, advanced-stage disease and reduced survival (17
). We have confirmed that the expression of VEGF had similar expression levels in low- and high-grade OSCs, maybe due to the alteration of fimbrial epithelial cells being an early event in the pathogenesis of high-grade OSCs and angiogenesis having not yet started.
p53 is a useful biomarker for detecting not only the early precursor lesions of high-grade OSCs, but also the later stages of this disease (19
). Lee et al
hypothesized that p53 signatures represent the elusive OSC precursor. In addition, short stretches of normal appearing Fallopian tube epithelium that strongly express p53, and in which p53 mutations have been identified in some cases, have been termed ‘p53 signatures’ (5
). Although these lesions may represent early events in serous carcinogenesis, it is not clear, at this time, whether p53 signatures are precursor lesions or if they are benign ‘reactive’ changes that overexpress p53 and have no biological relevance to neoplasia. It has been shown that the expression of p53 mutations was similar between the fimbriae of normal appearance of low- and high-grade OSCs in our study. It is possible that p53 mutations were preceded by other neoplastic changes of cells, maybe after the increase of pAKT and COX-2 and the decrease of E-cadherin; this is an area that requires further investigation.
The present study has limitations, including its retrospective design, which is prone to selection bias, and a small sample size. In addition, the technique of immunohistochemistry does not always reflect the structure and functionality of the protein.
In conclusion, our results showed that the immunostaining of pAKT and COX-2 were significantly higher in the fimbriae of normal appearance of high-grade OSCs than those of low-grade OSCs and that the immunostaining of E-cadherin was significantly higher in the fimbriae of low-grade OSCs than those of high-grade OSCs. The remaining 3 markers (MMP-2, VEGF and p53) had similar expression levels in low- and high-grade OSCs. The relative importance of the Fallopian tube compared with the ovarian surface epithelium in the genesis of high-grade serous ovarian cancers is still being debated. However, our results suggest marked biological differences in the behavior of the fimbriae in high- and low-grade OSCs and indicate that the proliferation, cell adhesion and inflammatory microenvironment of fimbriae of high-grade OSCs without STIC had changed prior to p53 mutation.