Changes in Gene Expression and Cellular Architecture in an Ovarian Cancer Progression Model

Abstract

BackgroundOvarian cancer is the fifth leading cause of cancer deaths among women. Early stage disease often remains undetected due the lack of symptoms and reliable biomarkers. The identification of early genetic changes could provide insights into novel signaling pathways that may be exploited for early detection and treatment.Methodology/Principal FindingsMouse ovarian surface epithelial (MOSE) cells were used to identify stage-dependent changes in gene expression levels and signal transduction pathways by mouse whole genome microarray analyses and gene ontology. These cells have undergone spontaneous transformation in cell culture and transitioned from non-tumorigenic to intermediate and aggressive, malignant phenotypes. Significantly changed genes were overrepresented in a number of pathways, most notably the cytoskeleton functional category. Concurrent with gene expression changes, the cytoskeletal architecture became progressively disorganized, resulting in aberrant expression or subcellular distribution of key cytoskeletal regulatory proteins (focal adhesion kinase, α-actinin, and vinculin). The cytoskeletal disorganization was accompanied by altered patterns of serine and tyrosine phosphorylation as well as changed expression and subcellular localization of integral signaling intermediates APC and PKCβII.Conclusions/SignificanceOur studies have identified genes that are aberrantly expressed during MOSE cell neoplastic progression. We show that early stage dysregulation of actin microfilaments is followed by progressive disorganization of microtubules and intermediate filaments at later stages. These stage-specific, step-wise changes provide further insights into the time and spatial sequence of events that lead to the fully transformed state since these changes are also observed in aggressive human ovarian cancer cell lines independent of their histological type. Moreover, our studies support a link between aberrant cytoskeleton organization and regulation of important downstream signaling events that may be involved in cancer progression. Thus, our MOSE-derived cell model represents a unique model for in depth mechanistic studies of ovarian cancer progression.

Discovery of microarray-identified genes associated with ovarian cancer progression

“…As a result, GEO has supporting data and links to almost 20,000 published manuscripts (35). In this study, the four microarray datasets used for the measurement of the six genes expression all were in compliance with published papers: GDS3592 (24), GDS3297 (25), GDS2785 (26) and GDS3894 (30). Cancer is frequently considered to be a disease of the cell cycle as alterations in different families of cell cycle regulators cooperate in tumor development.…”

“…Mouse ovarian surface epithelial (MOSE) cells at various stages (early and late) as they transition from a pre-neoplastic/non-malignant state to a malignant/invasive state provide a useful model (30). As shown in Fig.…”

Enhanced contactless dielectrophoresis enrichment and isolation platform via cell-scale microstructures

“…42,43 The MOSE-L FFLv used in this study is a highly aggressive cell type generated by intraperitoneal injection of tumorigenic MOSE cells (MOSE-L) into syngeneic mice and recovery of cells in the ascites; injection of MOSE-L FFLv results in rapidly developing tumors, 44,45 therefore suggesting TIC character. 46 For the purpose of this study, cells were cultured in DMEM (Sigma Aldrich, St. Louis, MO) supplemented with 4% of FBS (Atlanta Biologicals, Flowery Branch, GA) and 100 lg/ml each of penicillin and streptomycin (Life Technologies, Carlsbad, CA) at 37 C in a humidified incubator with 5% CO 2 .…”

Investigating dielectric properties of different stages of syngeneic murine ovarian cancer cells

“…Addressing the lack of adequate cell models, Roberts et al established a progressive mouse ovarian surface epithelial (MOSE) cell model by isolating and culturing ovarian surface epithelial cells; the cells spontaneously transform and progress from a premalignant nontumorigenic to a highly aggressive malignant phenotype. 4,5 This MOSE model enables the study of cellular and molecular changes in different stages of syngeneic ovarian cancer to determine regulatory mechanisms that may drive cancer progression and as such potential targets for cancer diagnosis and treatment. 4 Four stages of the disease were established based on their geno-and phenotype: early (MOSE-E), early intermediate (MOSE-E/I), intermediate (MOSE-I), and late (MOSE-L) cells.…”

“…5,6 Some of these differences can lead to distinctions in these cells' electrical properties. It has been reported previously that oral squamous cell carcinomas have distinctly different electrical properties than more normal keratinocyte populations, 7 primary normal keratinocytes, pre-cancerous, dysplastic cells, 8 and non-cancer-derived oral epithelial cells.…”