Regulation of invasion and peritoneal dissemination of ovarian cancer by mesothelin manipulation

Abstract

Peritoneal dissemination is a particular form of metastasis typically observed in ovarian cancer and the major cause for poor patient's outcome. Identification of the molecular players involved in ovarian cancer dissemination can offer an approach to develop treatment strategies to improve clinical prognosis. Here, we identified mesothelin (MSLN) as a crucial protein in the multistep process of peritoneal dissemination of ovarian cancer. We demonstrated that MSLN is overexpressed in primary and matched peritoneal metastasis of high-grade serous carcinomas (HGSC). Using several genetically engineered ovarian cancer cell lines, resulting in loss or gain of function, we found that MSLN increased cell survival in suspension and invasion of tumor cells through the mesothelial cell layer in vitro. Intraperitoneal xenografts established with MSLN high ovarian cancer cell lines showed enhanced tumor burden and spread within the peritoneal cavity. These findings provide strong evidences that MSLN is a key player in ovarian cancer progression by triggering peritoneal dissemination and provide support for further clinical investigation of MSLN as a therapeutic target in HGSC.

Generation of Two Paclitaxel-Resistant High-Grade Serous Carcinoma Cell Lines With Increased Expression of P-Glycoprotein

“…Our results show that OVCAR8 PTX R variants have similar levels of proliferation and cell viability in culture, maintaining the apoptotic level, anoikis resistance, and migratory capacity when compared to the parental OVCAR8 cell line. OVCAR8 is a Carboplatin-resistant cell line, with an intrinsic high proliferation index, resistance to anoikis and clonogenic survival, and migration capacity ( 37 , 40 ). These results demonstrate that the main features of the parental OVCAR8 cell line were maintained and the induced PTX resistance did not intensify these original cellular characteristics.…”

“…To evaluate cell proliferation, MTT [3-(4.5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium] assay was performed as previously described ( 40 ). Briefly, 1 × 10 3 cells/well were seeded into a 96-well plate in complete media and incubated at 37°C and 5% CO 2 up to 6 days.…”

“…To evaluate anoikis resistance, an aggregate formation assay was performed as previously described ( 40 ). Briefly, 1 × 10 6 cells/well were seeded into polyHEMA (Poly2-hydroxyethyl methacrylate; Sigma-Aldrich)-coated plates and incubated at 37°C and 5% CO 2 up to 15 days.…”

“…To evaluate cell proliferation, MTT [3-(4.5-Dimethylthiazol-2yl)-2,5-diphenyltetrazolium] assay was performed as previously described (40). Briefly, 1 × 10…”

Ovulatory Follicular Fluid Facilitates the Full Transformation Process for the Development of High-Grade Serous Carcinoma

“…Over the past two decades, after the paradigm related to the origin of ovarian cancer has shifted from the ovarian surface to the tubal epithelium, several mechanistic evidences supporting the transformation activity of ovulation, specifically the carcinogens released from the ovulation follicle, are available [ 20 , 21 , 22 , 35 , 36 , 37 ]. Research focusing on the molecular mechanism of ovarian and peritoneal metastasis is also rising [ 38 , 39 , 40 , 41 , 42 ]. However, whether incessant ovulation also enhances peritoneal or ovarian metastasis is unknown.…”