- Title
- Molecular analysis of early-stage ovarian cancer
- Creator
- Venkata, Varshini Devarapalli
- Relation
- University of Newcastle Research Higher Degree Thesis
- Resource Type
- thesis
- Date
- 2023
- Description
- Research Doctorate - Doctor of Philosophy (PhD)
- Description
- Ovarian cancer (OC) is one of the deadliest gynecological diseases with a 5-year survival rate of less than 45% [1]. Globally, 240,000 women are diagnosed with OC every year and currently there is no early diagnostic test [2]. Several risk factors have been identified and associated with OC over the past few years. Women with a family history of OC are at higher risk of the disease [3]. Mutations in the BRCA genes are linked with a high proportion of hereditary cancers [4]. Additionally, BRCA2 mutation carriers have an estimated 10-20% risk of developing OC by age 70, compared to 40-50% for BRCA1 [5]. On the contrary, women who have given birth have a reduced risk of OC [6, 7]. Breast feeding and oral contraceptives have also shown to reduce the risk of OC by 20-25% and 30% respectively [8-10]. Despite all these observations, the origin and early development of OC largely remains unknown because OC does not resemble the ovary. Instead, the four main histological subtypes of Epithelial Ovarian Cancer (EOC) bear strong resemblance to the normal cells lining different organs in the female reproductive tract (FRT) derived from the precursor Müllerian duct (MD) [11]. Therefore, this suggests that ovarian cancer might possibly develop from MD derived tissues and not the ovarian surface [12, 13]. Therefore, understanding the development of the MD into the female reproductive tract could give us insights into how ovarian cancer develops. In this thesis, we have established multiple models to study and understand the development of the MD in mouse and human. We characterized and established human fetal organoids as a model system to study the differences between fetal and adult fallopian tube and uterine epithelium. We utilized proteomic and histological analyses to tease apart the finer details of fetal fallopian tube and uterine epithelium in comparison to the adult. Finally, we used the fetal organoids to test their regenerative capacity by recellularising an adult scaffold. The human fetal organoid model and human fetal organoid-scaffold model can be easily manipulated to study Müllerian duct anomalies (MDAs), by using various growth factors to modulate signaling pathways. Secondly, we developed a mouse model to study MD development in its native environment. We established an organ culture system that consists of stroma as well as epithelium to study their interaction. This model can also be manipulated using a cocktail of growth factors to visualize the changes taking place on a daily basis. Finally, we wanted to study how the FRT further develops after birth to understand endometrioid ovarian cancer (EOVC) using a mouse model. For this we used immunofluorescence and proteomic analyses to decipher the various proteins and their signaling pathways involved in the formation of uterine glands postnatally as gland formation is commonly observed in EOVCs. In conclusion, we have established invaluable human and mouse models to study the development of the FRT which in turn will assist in decoding the oncogenesis of ovarian cancer.
- Subject
- mullerian duct; fallopian tube; uterus; Mullerian duct anomalies; ovarian cancer
- Identifier
- http://hdl.handle.net/1959.13/1484970
- Identifier
- uon:51462
- Rights
- Copyright 2023 Varshini Devarapalli Venkata
- Language
- eng
- Full Text
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| Thumbnail | File | Description | Size | Format | |||
|---|---|---|---|---|---|---|---|
| View Details Download | ATTACHMENT01 | Thesis | 7 MB | Adobe Acrobat PDF | View Details Download | ||
| View Details Download | ATTACHMENT02 | Abstract | 277 KB | Adobe Acrobat PDF | View Details Download |