- Title
- Genesis of ovarian cancer: understanding the mechanisms of oviductal epithelial cell homoeostasis
- Creator
- Ghosh, Arnab
- Relation
- University of Newcastle Research Higher Degree Thesis
- Resource Type
- thesis
- Date
- 2019
- Description
- Research Doctorate - Doctor of Philosophy (PhD)
- Description
- Fallopian tube (FT) (also known as oviduct in mouse) is a tubular structure that connects the ovary with the uterus. It is an important part of the female reproductive tract (FRT), as it provides the site for fertilisation inside its lumen. There are two separate events around the process of fertilisation, which are known as pre- and post-fertilisation event. The pre-fertilisation event requires the successful transfer of the healthy and viable gametes into the site of fertilisation to form an embryo. Whereas, the post-fertilisation event entails with embryo survival and successful embryo transport into the uterus for implantation. All these processes require an efficient function of every epithelial cell of FT lumen because they are in direct contact with the gametes and the embryo. Studies showed the faulty function of this epithelium leads to multiple reproductive disorders such as infertility, ectopic pregnancy and ovarian cancer. Clinical examination revealed that the FT epithelium of BRCA1/2 germline mutated patients who are more susceptible to ovarian cancer consist of the secretory cell only precancerous lesions. Thus in requirement of understanding this disease biology, there is a need to understand the healthy FT epithelial homeostasis first. Therefore, in my thesis, first I identified secretory cells as the stem/progenitor cells of mouse FT epithelium by using lineage tracing approach. This secretory cells can self-renew and differentiate into the ciliated cell to maintain the FT epithelial homeostasis. Upon identification of a stem/progenitor cell population, there is a need to identify the signalling pathways that are involved in the process of stem/progenitor cell self-renewal and differentiation. In the same chapter (Chapter 2), we also identified the Wnt/β-Catenin signalling pathway that guides the secretory cell self-renewal and stemness. We have provided evidence for the Wnt/β-Catenin signalling involvement in ciliated cell differentiation process (Chapter 3). We showed the role of Wnt/β-Catenin signalling pathway is indispensable for ciliated cell differentiation in mouse oviduct epithelium. Cells in the FRT are highly sensitive to ovarian steroid hormones such as estrogen and progesterone. Fluctuations in these hormones level during the oestrous/menstrual cycle also alter the morphology of the FT epithelial cells. In chapter 4, we showed the effect of ovarian hormone estrogen for a single epithelial cell fate determination. Our result showed estrogen could induce ciliated cell differentiation in mouse oviduct epithelium. However, the underlying mechanism of this estrogen-mediated ciliated cell differentiation has been remained unclear. We showed in the absence of the Wnt/β-catenin signalling pathway, estrogen do not induce any ciliated cell differentiation in the mouse oviduct epithelium. Overall, my thesis first time identified a stem/progenitor cell population in the mouse oviduct epithelium. Later we also defined the requirement of Wnt/β-catenin signalling pathway for the process of these stem/progenitor cell self-renewal and differentiation in mouse oviduct epithelium. In addition, we also proved in mouse oviduct signals from the Wnt pathway are the link between estrogen and ciliated cell differentiation process.
- Subject
- fallopian tube; β-Catenin; oviduct; ovarian cancer; hormone
- Identifier
- http://hdl.handle.net/1959.13/1405617
- Identifier
- uon:35526
- Rights
- Copyright 2019 Arnab Ghosh
- Language
- eng
- Full Text
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| Thumbnail | File | Description | Size | Format | |||
|---|---|---|---|---|---|---|---|
| View Details Download | ATTACHMENT01 | Thesis | 6 MB | Adobe Acrobat PDF | View Details Download | ||
| View Details Download | ATTACHMENT02 | Abstract | 188 KB | Adobe Acrobat PDF | View Details Download |