NLRC5 overexpression in ovarian tumors remodels the tumor microenvironment and increases T-cell reactivity toward autologous tumor-associated antigens.

Introduction: Epithelial ovarian cancer (OC) stands as one of the deadliest gynecologic malignancies, urgently necessitating novel therapeutic strategies. Approximately 60% of ovarian tumors exhibit reduced expression of major histocompatibility complex class I (MHC I), intensifying immune evasion mechanisms and rendering immunotherapies ineffective. NOD-like receptor CARD domain containing 5 (NLRC5) transcriptionally regulates MHC I genes and many antigen presentation machinery components.

PAX2 induces vascular-like structures in normal ovarian cells and ovarian cancer.

In adult tissue, the paired box 2 (PAX2) protein is expressed in healthy oviductal, but not normal ovarian surface epithelial cells. PAX2 is expressed in a subset of cases of serous ovarian carcinoma; however, the role of PAX2 in the initiation and progression of ovarian cancer remains unknown. The aim of the present study was to determine the biological effects of PAX2 expression in normal and cancerous epithelial cells.

PAX2 promotes epithelial ovarian cancer progression involving fatty acid metabolic reprogramming.

Ovarian cancer is the fifth most common type of cancer afflicting women and frequently presents at a late stage with a poor prognosis. While paired box 2 (PAX2) expression is frequently lost in high‑grade serous ovarian cancer, it is expressed in a subset of ovarian tumors and may play a role in tumorigenesis. This study investigated the expression of PAX2 in ovarian cancer.

COX2 is induced in the ovarian epithelium during ovulatory wound repair and promotes cell survival†.

The ovarian surface epithelium (OSE) is a monolayer of cells surrounding the ovary that is ruptured during ovulation. After ovulation, the wound is repaired, however, this process is poorly understood. In epithelial tissues, wound repair is mediated by an epithelial-to-mesenchymal transition (EMT).

GREB1 is an estrogen receptor-regulated tumour promoter that is frequently expressed in ovarian cancer.

Estrogenic hormone replacement therapy increases the risk of developing ovarian cancer, and estrogen promotes tumour initiation and growth in mouse models of this disease. GREB1 (Growth regulation by estrogen in breast cancer 1) is an ESR1 (estrogen receptor 1)-upregulated protein which may mediate estrogen action. GREB1 knockdown prevents hormone-driven proliferation of several breast and prostate cancer cell lines and prolongs survival of mice engrafted with ovarian cancer cells, but its mechanism of action remains unclear.

PAX2 maintains the differentiation of mouse oviductal epithelium and inhibits the transition to a stem cell-like state.

Recent studies have provided evidence that the secretory cells of the fallopian tube (oviduct) are a probable origin for high-grade serous ovarian carcinoma. In addition to secretory cells, the fallopian tube epithelium consists of ciliated cells and CD44+ undifferentiated stem-like cells. Loss of PAX2 expression is recognized as an early event in epithelial transformation, but the specific role of PAX2 in this transition is unknown.

Enhancing Expression of Functional Human Sodium Iodide Symporter and Somatostatin Receptor in Recombinant Oncolytic Vaccinia Virus for In Vivo Imaging of Tumors.

Unlabelled: Oncolytic virus (OV) therapy has emerged as a novel tool in our therapeutic arsenals for fighting cancer. As a live biologic agent, OV has the ability to target and selectively amplify at the tumor sites. We have reported that a vaccinia-based OV (Pexa-Vec) has shown good efficacy in preclinical models and in clinical trials.

Divergent Roles of PAX2 in the Etiology and Progression of Ovarian Cancer.

PAX2 is an essential transcription factor for development. Aberrant PAX2 expression in adult tissues is associated with carcinogenesis and experimental evidence shows that PAX2 generally exhibits oncogenic properties. Although PAX2 is not expressed in normal ovaries, it is highly expressed in low malignant potential and low-grade epithelial ovarian tumors, suggesting that PAX2 induction in ovarian surface epithelium (OSE) may contribute to transformation.

Microtubule disruption synergizes with oncolytic virotherapy by inhibiting interferon translation and potentiating bystander killing.

In this study, we show that several microtubule-destabilizing agents used for decades for treatment of cancer and other diseases also sensitize cancer cells to oncolytic rhabdoviruses and improve therapeutic outcomes in resistant murine cancer models. Drug-induced microtubule destabilization leads to superior viral spread in cancer cells by disrupting type I IFN mRNA translation, leading to decreased IFN protein expression and secretion. Furthermore, microtubule-destabilizing agents specifically promote cancer cell death following stimulation by a subset of infection-induced cytokines, thereby increasing viral bystander effects.

Optimization of lentiviral vector production using polyethylenimine-mediated transfection.

The aim of the present study was to optimize the polyethylenimine (PEI)-mediated transfection method in order to simplify the efficient production of lentiviral vectors (LvVs), and to compare the CaPO- and PEI-mediated transfection methods for producing LvVs. Different titration methods of LvV stocks, as well as different culture media, culture durations, cell densities and DNA quantities were compared to obtain an optimized procedure for the production of LvVs. Optimization of the production method for LvVs was achieved using PEI-mediated transient transfections.

Epithelial ovarian cancer stem cells: underlying complexity of a simple paradigm.

The lack of significant progress in the treatment of epithelial ovarian cancer (EOC) underscores the need to gain a better understanding of the processes that lead to chemoresistance and recurrence. The cancer stem cell (CSC) hypothesis offers an attractive explanation of how a subpopulation of cells within a patient's tumour might remain refractory to treatment and subsequently form the basis of recurrent chemoresistant disease. This review examines the literature defining somatic stem cells of the ovary and fallopian tube, two tissues that give rise to EOC.

A new spontaneously transformed syngeneic model of high-grade serous ovarian cancer with a tumor-initiating cell population.

Improving screening and treatment options for patients with epithelial ovarian cancer has been a major challenge in cancer research. Development of novel diagnostic and therapeutic approaches, particularly for the most common subtype, high-grade serous ovarian cancer (HGSC), has been hampered by controversies over the origin of the disease and a lack of spontaneous HGSC models to resolve this controversy. Over long-term culture in our laboratory, an ovarian surface epithelial (OSE) cell line spontaneously transformed OSE (STOSE).

Detrimental effects of acute hyperglycaemia on the rat heart.

Aim: Hyperglycaemia is an important risk factor for acute myocardial infarction. It can lead to increased induction of non-oxidative glucose pathways (NOGPs) - polyol and hexosamine biosynthetic pathways, advanced glycation end products and protein kinase C - that may contribute to cardiovascular diseases onset. However, the precise underlying mechanisms remain poorly understood.

Technical challenges and limitations of current mouse models of ovarian cancer.

The development of genetically engineered models (GEM) of epithelial ovarian cancer (EOC) has been very successful, with well validated models representing high grade and low grade serous adenocarcinomas and endometrioid carcinoma (EC). Most of these models were developed using technologies intended to target the ovarian surface epithelium (OSE), the cell type long believed to be the origin of EOC. More recent evidence has highlighted what is likely a more prevalent role of the secretory cell of the fallopian tube in the ontogeny of EOC, however none of the GEM of EOC have demonstrated successful targeting of this important cell type.

Harnessing oncolytic virus-mediated antitumor immunity in an infected cell vaccine.

Treatment of permissive tumors with the oncolytic virus (OV) VSV-Δ51 leads to a robust antitumor T-cell response, which contributes to efficacy; however, many tumors are not permissive to in vivo treatment with VSV-Δ51. In an attempt to channel the immune stimulatory properties of VSV-Δ51 and broaden the scope of tumors that can be treated by an OV, we have developed a potent oncolytic vaccine platform, consisting of tumor cells infected with VSV-Δ51. We demonstrate that prophylactic immunization with this infected cell vaccine (ICV) protected mice from subsequent tumor challenge, and expression of granulocyte-monocyte colony stimulating factor (GM-CSF) by the virus (VSVgm-ICV) increased efficacy.

A selectable and excisable marker system for the rapid creation of recombinant poxviruses.

Background: Genetic manipulation of poxvirus genomes through attenuation, or insertion of therapeutic genes has led to a number of vector candidates for the treatment of a variety of human diseases. The development of recombinant poxviruses often involves the genomic insertion of a selectable marker for purification and selection purposes. The use of marker genes however inevitably results in a vector that contains unwanted genetic information of no therapeutic value.

17beta-estradiol accelerates tumor onset and decreases survival in a transgenic mouse model of ovarian cancer.

Epithelial ovarian cancer is thought to be derived from the ovarian surface epithelium (OSE) but often goes undetected in the early stages, and as a result, the factors that contribute to its initiation and progression remain poorly understood. Epidemiological studies have suggested that the female steroid hormones are involved in ovarian carcinogenesis and that women who use hormone replacement therapy are at increased risk of developing the disease. A novel transgenic mouse model of ovarian cancer (tgCAG-LS-TAg) was developed to examine the role of the female reproductive steroid hormones [17beta-estradiol (E(2)) and progesterone (P(4))] on the initiation, progression, and pathology of ovarian cancer.

[The mouse ovarian surface epithelium cells (MOSE) transformation induced by c-myc/K-ras in].

Objective: To study the function of c-myc and K-ras in tumorigenesis of ovarian cancer.

Methods: K-ras and/or c-myc cDNAs were introduced into mouse ovarian surface epithelium cells (MOSE) using recombinant Moloney retroviral vectors. The resulting MOSE cells were studied by cell proliferation assays, the ability to form colonies in soft agarose, matrigel invasion assays and tumorigenicity assays in nude mice.

Conditional inactivation of Brca1 in the mouse ovarian surface epithelium results in an increase in preneoplastic changes.

Epithelial ovarian cancer (EOC) is thought to arise from the ovarian surface epithelium (OSE); however, the molecular events underlying this transformation are poorly understood. Germline mutations in the BRCA1 tumor suppressor gene result in a significantly increased risk of developing EOC and a large proportion of sporadic EOCs display some sort of BRCA1 dysfunction. Using mice with conditional expression of Brca1, we inactivated Brca1 in the murine OSE and demonstrate that this inactivation results in the development of preneoplastic changes, such as hyperplasia, epithelial invaginations, and inclusion cysts, which arise earlier and are more numerous than in control ovaries.

[*OPCML gene transferred by recombinant lentiviruses in vitro and its inhibition to ovarian cancer cells].

Objective: To study the inhibition of OPCML on ovarian cancer cell lines using a lentiviral vector system for efficient gene transduction.

Methods: The murine OPCML cDNA was amplified by PCR from CD1 murine brain cDNA using gene specific primers, and subcloned into the lentiviral vector, pWPI-GFP, to generate the lentiviral expression vector, pWPI-OPCML. Recombinant lentiviruses were produced by 293T cells following the co-transfection of pWPI-OPCML, with the packaging plasmids pCMV-dR8.

Models of ovarian cancer--are we there yet?

Ovarian cancer is the most lethal of all gynecological cancers and arises most commonly from the surface epithelium. Successful clinical management of patients with epithelial ovarian cancer is limited by the lack of a reliable and specific method for early detection, and the frequent recurrence of chemoresistant disease. Experimental models are of crucial importance not only to understand the biological and genetic factors that influence the phenotypic characteristics of the disease but also to utilize as a basis for developing rational intervention strategies.

Translational research in ovarian cancer: a must.

Ovarian cancer discovered at late clinical stage continues to be a fatal disease. It seems self-evident that if we are to make an impact on the survival of advanced ovarian cancer patients, we must begin to understand the disease more completely. This should improve the diagnosis of the disease at an early stage when it is curable by surgery or develop better/targeted drug treatments.

Generation of tumors in transgenic mice expressing the SV40 T antigen under the control of ovarian-specific promoter 1.

Objective: The ovarian-specific promoter, OSP-1, which was cloned from the transcript of a rat retrovirus-like element specifically expressed in ovarian tissue, was tested for its ability to drive ovary-specific transcription in transgenic mice.

Methods: Transgenic mice were generated with the lacZ reporter gene (OSP-lacZ) or the early region of SV40 virus (OSP-TAg) placed under the control of the OSP-1 promoter. OSP-lacZ and OSP-TAg transgenic animals were examined, respectively, for the expression of lacZ (OSP-lacZ) or the development of tumors (OSP-TAg).

Oncolytic viruses: programmable tumour hunters.

Despite significant improvements in early detection and refinements of therapeutic protocols over the last several decades, cancer remains one of the leading causes of death in North America. In particular, treatment of metastatic cancers is a highly desirable and yet still elusive goal of the oncologist. One strategy which holds promise is the use of self replicating viral strains with the ability to specifically kill tumour but not normal cells.