Molecular Mechanisms Regulating Organ-Specific Metastases in Epithelial Ovarian Carcinoma

Epithelial ovarian carcinoma is the most predominant type of ovarian carcinoma, the deadliest gynecologic malignancy. It is typically diagnosed late when the cancer has already metastasized. Transcoelomic metastasis is the most predominant mechanism of dissemination from epithelial ovarian carcinoma, although both hematogenously and lymphogenously spread metastases also occur. In this review, we describe molecular mechanisms known to regulate organ-specific metastasis from epithelial ovarian carcinoma. We begin by discussing the sites colonized by metastatic ovarian carcinoma and rank them in the order of prevalence. Next, we review the mechanisms regulating the transcoelomic metastasis. Within this chapter, we specifically focus on the mechanisms that were demonstrated to regulate peritoneal adhesion—one of the first steps in the transcoelomic metastatic cascade. Furthermore, we describe mechanisms of the transcoelomic metastasis known to regulate colonization of specific sites within the peritoneal cavity, including the omentum. Mechanisms underlying hematogenous and lymphogenous metastatic spread are less comprehensively studied in ovarian cancer, and we summarize mechanisms that were identified to date. Lastly, we discuss the outcomes of the clinical trials that attempted to target some of the mechanisms described in this review

Targeting Microtubule-Associated Protein Tau in Chemotherapy-Resistant Models of High-Grade Serous Ovarian Carcinoma

Relapsed, recurrent, chemotherapy-resistant high-grade serous ovarian carcinoma is the deadliest stage of this disease. Expression of microtubule-associated protein tau (tau) has been linked to resistance to paclitaxel treatment. Here, I used models of platinum-resistant and created models of platinum/paclitaxel-resistant high-grade serous ovarian carcinoma to examine the impact of reducing tau expression on cell survival and tumor burden in cell culture and xenograft and syngeneic models of the disease. Tau was overexpressed in platinum/paclitaxel-resistant models; expression of phosphoSer396 and phosphoThr181 species was also found. A treatment with leucomethylene blue reduced the levels of tau in treated cells, was cytotoxic in cell cultures, and efficiently reduced the tumor burden in xenograft models. Furthermore, a combination of leucomethylene blue and paclitaxel synergized in eliminating cancer cells in cell culture and xenograft models. These findings underscore the feasibility of targeting tau as a treatment option in terminal-stage high-grade serous ovarian cancer

Expression and Function of CD44 in Epithelial Ovarian Carcinoma

CD44, a cell surface glycoprotein, has been increasingly implicated in the pathogenesis and progression of epithelial ovarian cancer, the deadliest gynecologic malignancy in women. Here, we review recent reports on the expression and function of CD44 in epithelial ovarian carcinoma. Further functional data for CD44 in peritoneal adhesion and metastatic progression and its association with stem cells is highlighted. Recent studies utilizing CD44 for therapeutic targeting are also discussed

The miR-200 Family: Versatile Players in Epithelial Ovarian Cancer

The role of microRNAs (miRNAs or miRs) in the pathology of epithelial ovarian cancer (EOC) has been extensively studied. Many miRNAs differentially expressed in EOC as compared to normal controls have been identified, prompting further inquiry into their role in the disease. miRNAs belonging to the miR-200 family have repeatedly surfaced over multiple profiling studies. In this review, we attempt to consolidate the data from different studies and highlight mechanisms by which these miRNAs influence progression of metastasis and chemo-resistance in EOC

Examination of the Fractalkine and Fractalkine Receptor Expression in Fallopian Adenocarcinoma Reveals Differences When Compared to Ovarian Carcinoma

Fallopian adenocarcinoma is a rare malignancy arising in the epithelium of the fallopian tube. Fallopian tube epithelium has been proposed as a tissue origin for high-grade serous ovarian carcinoma, the deadliest gynecologic malignancy. Given the commonalities in dissemination and treatment of these malignancies, we contemplated the possibility of similar patterns of gene expression underlying their progression. To reveal potential similarities or differences in the gene expression of fallopian adenocarcinoma and high-grade serous ovarian carcinoma, we tested expression of the fractalkine receptor (CX3CR1) and its ligand, fractalkine (CX3CL1), in the specimens of normal and pathologic fallopian tube using immunohistochemistry. Our data show that CX3CR1 is expressed in the normal, cancer adjacent normal, inflammatory, and malignant fallopian epithelium. CX3CL1 was expressed only by the normal and cancer adjacent normal fallopian tube epithelium; its expression was largely lost in the inflammatory and malignant fallopian epithelium. In opposite, both CX3CR1 and CX3CL1 are expressed in high-grade serous ovarian carcinoma. These findings are consistent with an idea that fallopian adenocarcinoma and high-grade serous ovarian carcinoma, although currently thought to arise from the same organ, may not share similar molecular characteristics

Three-Dimensional Collagen Type I Matrix Up-Regulates Nuclear Isoforms of the Microtubule Associated Protein Tau Implicated in Resistance to Paclitaxel Therapy in Ovarian Carcinoma

Epithelial ovarian carcinoma is the deadliest gynecologic malignancy. One reason underlying treatment failure is resistance to paclitaxel. Expression of the microtubule associated protein tau has recently been proposed as a predictor of response to paclitaxel in ovarian carcinoma patients. Expression of tau was probed using immunohistochemistry in 312 specimens of primary, and 40 specimens of metastatic, ovarian carcinoma. Serous epithelial ovarian carcinoma cell line models were used to determine the expression of tau by Western blot and immunofluorescence staining. Subcellular fractionation and Western blot were employed to examine nuclear and cytoplasmic localization of tau. Gene silencing and clonogenic assays were used to evaluate paclitaxel response. Tau was expressed in 44% of all tested cases. Among the primary serous epithelial ovarian carcinoma cases, 46% were tau-positive. Among the metastatic serous epithelial ovarian carcinomas, 63% were tau-positive. Cell culture experiments demonstrated that tau was expressed in multiple isoforms. Three-dimensional collagen I matrix culture conditions resulted in up-regulation of tau protein. Silencing of tau with specific siRNAs in a combination with three-dimensional culture conditions led to a significant decrease of the clonogenic ability of cells treated with paclitaxel. The data suggest that reduction of tau expression may sensitize ovarian carcinoma to the paclitaxel treatment

Fractalkine receptor is expressed in mature ovarian teratomas and required for epidermal lineage differentiation

BACKGROUND: The goal of this study was to determine a predominant cell type expressing fractalkine receptor (CX3CR1) in mature ovarian teratomas and to establish functional significance of its expression in cell differentiation. METHODS: Specimens of ovarian teratoma and human fetal tissues were analyzed by immunohistochemistry for CX3CR1expression. Ovarian teratocarcinoma cell line PA-1 was used as a model for cell differentiation. RESULTS: We found that the majority of the specimens contained CX3CR1-positive cells of epidermal lineage. Skin keratinocytes in fetal tissues were also CX3CR1- positive. PA-1 cells with downregulated CX3CR1 failed to express a skin keratinocyte marker cytokeratin 14 when cultured on Matrigel in the presence of a morphogen, bone morphogenic protein 4 (BMP-4), as compared to those expressing scrambled shRNA. CONCLUSIONS: Here we demonstrate that CX3CR1 is expressed in both normally (fetal skin) and abnormally (ovarian teratoma) differentiated keratinocytes and is required for cell differentiation into epidermal lineage