Ken Garson, Ph.D., Research Associate
One important research direction that will advance our understanding of ovarian cancer and generate tools for the pre-clinical evaluation of new therapeutics is the development of transgenic mouse models of ovarian cancer. The first major challenge to developing these models was the targeting of oncogene expression to the ovarian surface epithelium, the layer of cells which gives rise to epithelial ovarian cancer. Our first two mouse models of epithelial ovarian cancer have met this challenge by directing oncogene (SV40 T antigen) expression directly to the ovary using either the MISIIR promoter (tgMISIIRTAg model) or by exploiting the cre/loxP recombination system to activate the expression of this same oncogene in the ovarian surface epithelium. In this latter model (tgCAG-LS-TAg model), conditional activation of the SV40 T antigen is achieved by the injection of AdCre (an adenovirus expressing cre recombinase) into the bursal space surrounding the ovary. Interestingly, the tgMISIIRTAg model offers “two models for the price of one” since the female mice reproducibly develop bilateral epithelial tumours of the ovary (with occasional peritoneal ascites and metastases) and the male mice develop tumours of the prostate. The tgMISIIRTAg female mice are well suited for the testing of novel therapeutics (see Valerie Snoulten) since they develop ovarian tumours with very reproducible kinetics. One disadvantage of this model is the appearance of nascent tumours in very young mice. The control and delay of tumourigenesis has been achieved in the tgCAG-LS-TAg model by the timed injection of AdCre. This permits the study of early disease and parameters that affect it (See Laura Laviolette). In addition to the continued characterization and exploitation of the above models, we have started to develop reagents for our next generation of models. The two major goals for our future models are to directly express or suppress genes with established roles in ovarian carcinogenesis and to modulate the differentiation of tumours into the different histological subtypes observed in the clinic.
Elizabeth MacDonald, M.Sc., Research Technician
I am a Senior Research Technician and have been a member of Dr. Vanderhyden's lab since 1995. I am responsible for managing and maintaining the many transgenic mouse lines which include our mouse models of ovarian cancer. Currently I am crossing a number of KO mouse lines onto our inducible tgCAG-LS-TAg ovarian cancer mouse model to investigate the effects of loss of expression upon tumor development. I also manage the Ottawa Ovarian Cancer Tissue Bank, which Dr. Vanderhyden's lab is responsible for. This involves collecting and processing ovarian tumor tissue for research purposes and maintaining corresponding records. Helping to train undergraduate and graduate students in cellular and molecular techniques, troubleshooting problematic assays and helping with the general day to day operations of the lab are some of the many duties of which I am involved in as a member of Dr. Vanderhyden's lab.
Olga Collins, B.Sc., Research Technician
I have been a research technician in Dr. Vanderhyden's lab since 2001. I form part of the mouse models of ovarian cancer group in our lab. My work focuses on the isolation, growth, and characterization of mouse ovarian surface epithelial cells and how they transform into ovarian cancer. With Curtis McCloskey and Lauren Carter, I am also exploring the possible existence of a progenitor cell population within the ovarian surface epithelium.
Kendra Hodgkinson, Ph.D. candidate
Investigating the role of menopause and hormone replacement therapy in ovarian cancer
Why do the risks of ovarian cancer rise after menopause? Why does hormone replacement therapy seem to increase your risk of developing this cancer? My project explores these questions by simulating menopause in a mouse model of ovarian cancer, and investigating the impact of reproductive hormones (estrogen, progesterone) on cancer progression in this model. I would like to see how ovarian changes associated with menopause may stimulate the initiation or progression of ovarian cancer, and how these menopausal changes are altered by hormone replacement therapy. Supported by a scholarship from the CIHR Training Program in Reproduction, Early Development, and the Impact on Health.
Nhung (Rose) Vuong, Ph.D. Candidate
Mechanisms by which estrogen accelerates onset of ovarian cancer
Estrogen is the primary steroid hormone that regulates female reproduction and secondary sex characteristics. The mechanisms by which it mediates its actions are complex, involving multiple receptor isoforms (ER?, ER?) and signaling pathways. Our lab has shown that increases in estrogen levels can accelerate the onset of ovarian cancer. The majority of ovarian cancers arise from the ovarian surface epithelium (OSE) or the adjacent epithelium of the distal fallopian tube. Loss of cell polarity is a hallmark of epithelial cancer as epithelial cells undergoing transformation into cancerous tissue lose their polarity and become hyperplastic. We hypothesize that estrogen suppresses expression of polarity genes in the OSE, leading to loss of polarity and hyperplasia that subsequently renders OSE more susceptible to transformation. My PhD project focuses on determining the effects of estrogen exposure on polarity genes in normal, immortalized, and cancerous mouse OSE cells and to determine if exogenous estrogen alters their expression during tumor development in a mouse model of ovarian cancer. Supported by a Queen Elizabeth II Graduate Scholarship in Science and Technology.
Kholoud Al-Wosaibai, Ph.D. candidate
Characterization of putative stem cells in fallopian tube epithelium as an origin of ovarian cancer.
Knowing the origins of ovarian cancer is very important for researchers to investigate risk factors. For more than 30 years, scientists have focused on ovarian surface epithelial cells (OSE) and the theory that the OSE gives rise to serous carcinoma was widely accepted. Recently, studies have provided evidence that oviductal epithelial cells (OVE) are a potential origin of serous carcinomas as well as OSE cells. This may be because of the close association between the ovary and fallopian tube in the reproductive system in women. A growing number of studies have focused on the OVE cells as a potential origin of ovarian cancer, but information about the transformation process in these cells is still limited. In my project, I am manipulating mouse OVE cells as a model to investigate the possible origins of ovarian cancer, using factors to induce Epithelial Mesenchymal Transition (EMT) and characterization of possible stem cells. The results will lead us to better understand the origin of ovarian cancer and may identify potential inhibitors of this disease.
Ensaf Alhejaily, Ph.D. Candidate
Role of PAX2 in the initiation of ovarian cancer,
Growing evidence supports two distinct types (low-grade or high-grade) of ovarian carcinogenesis. Both types have distinct molecular profiles, pathological features and clinical outcomes. The pathogenesis of ovarian cancer is poorly elucidated and the origin of ovarian cancer is not yet clear. The cancers appear to develop through a process that includes the formation of a transitional, preneoplastic structure that is characterized by increased proliferation and reduced cell death of precursor cells. Recent characterization of these preneoplastic structures implicates altered expression of several genes including the transcription factor PAX2. PAX2 is normally expressed during development. However, its expression in adult tissue is attenuated with the exception of the uterus, cervix and fallopian tube. Interestingly, it is not expressed in normal ovaries but highly expressed in low grade ovarian serous carcinoma. Although Pax2 has been suggested to be potential proto-oncogene, the exact mechanism by which PAX2 elicits tumorigenesis in not known. My PhD project investigates the consequences of PAX2 induction in normal epithelium of the ovaries. I am trying to determine if PAX2 initiates tumorigenesis either alone, or in combination with other mutations including p53 deletion. The other part of my project is to identify if PAX2 enhances tumorigenesis in murine or human cancer cell lines, by making them more proliferative and resistant to chemotherapy.
Lauren Carter, M.Sc. Candidate
Ovarian stem cells and their role in ovulatory wound repair.
I have recently begun my Master?s degree working on ovarian stem cells and their role in ovulatory wound repair. The ovarian surface epithelium (OSE) is a single layer of epithelial cells surrounding the ovary which is ruptured during ovulation. After ovulation, the ovulatory wound is repaired, although the processes involved and the consequences of improper healing are poorly understood. The OSE is one tissue of origin of ovarian cancer and ovulation is its primary nonhereditary risk factor. We have shown that the OSE contain cells exhibiting progenitor/stem cell characteristics and exposure to factors found in the follicular fluid increases these characteristics. This indicates these progenitor cells may play a role in ovulatory wound repair. My project involves examining the effects of TGF? (a factor found in the follicular fluid) and ovulation on regulation of the OSE stem/progenitor cell population.
Curtis McCloskey, M.Sc. Candidate
The role of ovulation-associated factors and Brca1 in the regulation of mOSE stemness, differentiation and, cancer.
Ovulation is one of the biggest risk factors in the development of ovarian cancer due to the constant need to repair the wound created by the ruptured follicle. Faulty wound-repair is thought to underlie the development of pre-malignant lesions, sites from which the tumor can develop. A second risk factor is a mutation in the gene BRCA1, or sporadic loss of function of the BRCA1 protein. BRCA1 is an enzyme with many critical roles in the cell and past work in our lab has shown that inactivation of Brca1 increases the number of pre-malignant lesions in the ovary. More recently, our lab has identified factors released during ovulation that can regulate a stem-like population on the surface of the ovary, implicating ovulatory factor signaling in the regulation of wound repair. Furthermore, recent work on breast cancer has established BRCA1 in the regulation of stem-like populations. Combining knowledge from the ovarian and breast cancer fields, I aim to study to links between ovulation and BRCA1 in the regulation of the stem-like population on the ovarian surface and, how this regulation when aberrant, could result in the initiation of ovarian cancer. Supported by an Ontario Graduate Scholarship.
Pascale Charette, M.Sc. Candidate
I obtained a Bachelor of Science specialized in Biomedical Science from the University of Ottawa in April 2013. My Honours project, also in the Vanderhyden lab, focused on the effect of estrogen on angiogenesis in ovarian tumors. In collaboration with the Andrée Gruslin lab, I currently investigate FGL2, a protein thought to be involved in preeclampsia, a potentially serious condition that develops in about 7% of pregnancies. In an attempt to develop a novel mouse model for preeclampsia, I am investigating the expression and function of FGL2 in mouse models and human placentae. Using techniques like immunohistochemistry and quantitative real-time PCR, I am currently assessing the expression and localization of FGL2 in the placentae and ovaries of these mice, and monitoring them for indicators of preeclampsia. Ultimately, the aim is to be able to use these mice to investigate how FGL2 levels can predict the occurrence and severity of preeclampsia in high-risk women.