| Ovarian cancer is a deadly cancer in human being. Although ovarian cancer accounts for only3%of all cancers in women, its death-to-incidence ratio is among the highest. This has primarily been attributed to the unavailability of effective screening tools and absence of specific clinical symptoms in early stages. Nearly204,000women worldwide are suffered with and125,000women are killed by ovarian cancer every year. In2012, it is estimated that22,280new cases of ovarian carcer will be diagnosed and about15,500patients will die of the disease in the United States. In our country, ovarian cancer has become the second most common tumor behind cervical cancer in gynecologic tract.The prognosis of ovarian cancer, just like other cancers, is closely associated with cancer stage. Therefore, effective early detection is necessary to improve the overall survival. However, the fact is that only15%of ovarian epithelial cancer (OEC) is diagnosed at stage â… , up to70%of OEC patients present at stage â…¢ or â…£. Attempts at screening and early detection of OEC, using a combination of pelvic examination, transvaginal ultrasounds, and measurements of serum CA-125, have largely been unsuccessful due to their lack of sufficient specificity and sensitivity in the general population. The reasons for this are that the concepts of carcinogenesis, on which these approaches are based, are flawed.Among various types of OECs, high-grade serous carcinoma (HG-SC) is the most common and deadly. Traditionally, HG-SC was thought to originate from ovarian surface epithelium (OSE) or ovarian epithelial inclusions (OEI). Recently, studies of both asymptomatic women with germline mutations of BRCA1and/or BRCA2and those from the general population with pelvic serous carcinoma have detected precancer or early cancerous lesions-serous tubal intraepithelial carcinoma (STIC)-in the tubal fimbria. Furthermore, latent precancerous lesion 'p53signature' and precancerous lesion dysplasia were also detected in the fimbira. These lesions overexpress p53and have some identical TP53mutations with ovarian HG-SC, which have significantly increased the insights into ovarian serous carcinogenesis. In contrast, there is no any convinced evidence showing precancerous lesions found within the ovary. From those studies, the fallopian tube has emerged as an important source for ovarian HG-SC, resulting in a paradigm shift that will have critical influences for future detection, therapy and prevention of OEC in near future.In contrast to HG-SC, ovarian low-grade serous carcinoma (LG-SC) is thought to develop in a stepwise fashion, sequentially from OEIs or serous cystadenoma, then to serous borderline tumor, and eventually to invasive carcinomas. Up to now, most people still believe that OEI originates from OSE. However, if the OEIs were truly originating from mesothelium-derived ovarian epithelial inclusions through a Mullerian metaplasia, the metaplastic process must be a common event and hybrid type of OEI should be commonly found in the ovary. The fact is that hybrid or intermediate type of OEIs with both mesothelial and tubal phenotypes is rarely found in our practice. Furthermore, the arguments against OSE as the origin of most OECs are similarly applicable to OEIs if it is assumed that OEIs are derived from OSE. Therefore, the LG-SC may also originate from the fallopian tube.Proteomics has emerged as a powerful technology to decipher biological processes. It denotes the large-scale characterization of proteins, including complicated features like isoforms, modifications, interactions, and functional structures. As the proteome in any cell represents a subset of all possible gene products, the genome is simpler than the proteome; any protein may exist in multiple forms that vary within a particular cell or in different cells. Modifications may derive from translational, post-translational, regulatory, and degradative processes that affect protein structure, localization, function, and turnover. Thus, proteomics can really reflect the function of tissues or cells.Based on the above rationale, the project included the following two parts.PART I MORPHOLOGICAL ANALYSIS OF THE CELL ORIGIN OF OVARIAN LOW-GRADE SEROUS CARCINOMABackground and Purpose:Ovarian cancer is the fifth most common cause of cancer death in women behind lung, breast, colorectal, and pancreatic cancers. In particular, patients with serous carcinoma (which constitute60-80%of ovarian epithelial carcinomas) are most frequently present at advanced clinical stage and have a very poor overall survival. Attempts at screening and early detection of ovarian cancer have largely been unsuccessful due to their lack of sufficient specificity and sensitivity in the general population. The reasons for this are that the concepts of carcinogenesis, on which these approaches are based, are flawed. Recent studies have shown that ovarian high-grade serous carcinoma originated from the fallopian tube. In contrast, what is the true cell origin of ovarian low-grade serous carcinoma? The current study was designed to gain insight into the possible origin of the low-grade serous carcinoma through the detailed analysis of the cell origin of ovarian epithelial inclusions and its relationship with the low-grade serous carcinoma.Material and Method:By comparatively evaluating the morphologic (secretory and ciliated cell distribution) and immunophenotypic (using PAX8, tubulin, calretinin, and Ki67as first antibodies) attributes of ovarian epithelial inclusions, the normal tubal epithelium, and the ovarian tumors, all adnexal tissues from a total of178patients were studied, including98adnexae removed for non-neoplastic indications,48serous cystadenomas,42serous borderline tumors, and38low-grade serous carcinomas.Result:The vast majority (100%,48/48) of ovarian surface epithelia displayed a mesothelial phenotype (calretinin+/PAX8-/tubulin-), whereas4%of the cases displayed foci with tubal phenotype (calretinin-/PAX8+/tubulin-). In contrast, most (78%,667/856) of the ovarian epithelial inclusions displayed a tubal phenotype with the proliferative index1.05%, although22%(188/856) of the ovarian epithelial inclusions showed a mesothelial phenotype with much lower proliferative index (0.12%). There was a progressive increase in the secretory/ciliated cell ratio and proliferative index, from ovarian epithelial inclusions/cystadenomas to borderline tumors to low-grade serous carcinoma.Conclusion:Although epithelia with a tubal phenotype were only found in4%cases, the finding did show that benign tubal epithelia are able to implant on the ovarian surface and architecturally simulate'ovarian surface epithelium'microscopically. The ovarian epithelial inclusions displaying a tubal phenotype are likely derived from fallopian tube rather than from ovarian surface epithelia through a metaplstic process. The increasing trend of secretory/ciliated cell ratio and proliferative index from ovarian epithelial inclusions/cystadenomas to borderline tumors to low-grade serous carcinoma indicates that the latter is a clonal expansion of secretory cells and secretory cell is the cell origin of ovarian low-grade serous carcinoma. PART â…¡ PROTEOMICS OF OVARIAN SEROUS CARCINOMA AND CARCINOGENESISBackground and Purpose:Recently, the fallopian tube has become an important origin site for ovarian cancer. Given it has been proved that the high-grade serous carcinoma mainly originates from the fallopian tube, what about other types of ovarian cancer? Based on the first part of our study, the morphological and immunohistochemistry results showed that ovarian low-grade serous carcinoma may also originate from the fallopian tube. As a result, we will further prove this possibility by comparing the fallopian tube and ovarian serous carcinoma with proteomics. Furthermore, some differentially expressed proteins between serous carcinoma and fallopian tube are selected for ovarian carcinogenesis study.Material and Method:10fallopian tubes,10serous cystadenomas,10low-grade serous carcinomas and10high-grade serous carcinomas were selected for proteomics analysis. In addition, primary culture cells of OSE were also used for analysis. Some different expressed proteins of ovarian serous carcinoma were analyzed and immunohistochemistry was used for validation.Result:The number of proteins which can be identified by proteomics in the five groups of ovarian tissue sources is in the following:7535for the fallopian tube,3562for the ovarian surface epithelium,4515for cystadenoma,6782for low-grade serous carcinoma and8453for high-grade serous carcinoma. Compared with fallopian tube or ovarian surface epithelium, the ovarian serous tumor was more similar with the fallopian tube. Some proteins which are specific expressed in fallopian tube are also detected in ovarian serous carcinoma, such as PAX8, HOXA9and EpCAM. In contrast, calretinin, one mesothelial marker, is only expressed in ovarian surface epithelium. Moreover, some different expressed proteins in ovarian serous carcinoma were selected, such as GTPase h-ras isoform1, DNA mismatch repair protein6, cyclin-dependent kinase inhibitor2A and C-terminal binding protein2, etc, which will provide some insights into ovarian carcinogenesis.Conclusion:The protein profile of ovarian serous carcinoma is more similar with that of fallopian tube, which gives further support that ovarian serous carcinomas including both high-grade and low-grade originate from the fallopian tube. Meanwhile, some differentially expressed proteins in ovarian serous carcinoma are selected for further studies in the process of ovarian epithelial carcinogenesis.
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