Diss. (sammanfattning) Stockholm : Karol. inst. / Härtill 5 uppsatser.

Thesis (M. Med. Sc.)--University of Hong Kong, 2002. / Includes bibliographical references (leaves 92-103).

Thesis (M.Med.Sc.)--University of Hong Kong, 2002. / Includes bibliographical references (leaves 92-103). Also available in print.

published_or_final_version / Medical Sciences / Master / Master of Medical Sciences

No description available.

Several studies have proposed the fallopian tube epithelium as a site of origin of ovarian cancer. The discovery of precursor lesions in the fallopian tube in patients at risk for ovarian cancer supports a probable origin for high-grade serous ovarian carcinoma in this tissue. While the fallopian tube epithelium consists of three distinct cell types, the paired box protein 2 (PAX2) positive cells and potentially the CD44 positive stem-like cells are most relevant to ovarian cancer. Loss of PAX2 expression in the fallopian tube cells is considered to be an early event in epithelial transformation, but the specific role of PAX2 in this transition is unknown. The aim of this study was to define the role of PAX2 in oviductal epithelial cells (OVE) cells and in mouse ovarian surface epithelial cells (MOSE), and to understand its contribution to the formation of serous precursor lesions in the fallopian tubes. Herein, we studied the OVE response to transforming growth factor β (TGFβ, a cytokine found in follicular fluid) and provide evidence of its potential involvement in the regulation of stem cell-like behaviors that may contribute to formation of cancer-initiating cells. Treatment of primary cultures of OVE cells with TGFβ at concentrations found in ovulatory follicular fluid induced an epithelial-mesenchymal transition (EMT) with expected changes in proliferation, cell morphology and expression of SNAIL, Vimentin and E-cadherin. EMT was also associated with decreased expression of PAX2 and an increase in the fraction of cells expressing CD44. Pax2 knockdown in OVE cells and overexpression in ovarian epithelial cells confirmed that PAX2 inhibits CD44 expression and regulates the degree of epithelial differentiation of OVE cells. These results suggest that the loss of PAX2 seen in serous tubal intraepithelial carcinomas (STIC) leads to a shift to a more mesenchymal phenotype associated with stem-like features. Pax2 overexpression in MOSE cells also induced the formation of vascular channels both in vitro and in vivo, which indicate a possible contribution of PAX2 to ovarian cancer progression by increasing the vascular channels to supply nutrients to the tumor cells. Furthermore, since loss of PAX2 in STIC was found associated with P53 and BRCA1 mutations, OVE cells with mutations of the tumor suppressor genes Trp53 and Brca1 were studied. We found that loss of Trp53 with or without loss of Brca1 increased cell proliferation and colony formation in vitro. In addition, loss of Trp53 induced OVE cells to undergo EMT and induced the expression of stem cell–associated genes. We therefore suggest a potential contribution of stem cells in initiating the precursor lesions in the fallopian tubes in combination with tumor suppressor gene mutation.

Both VEGF and its receptor proteins were localized by immunostaining technique in the luminal epithelium, smooth muscle cells and blood vessels within the oviduct. Moreover, by means of semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) techniques, it has been demonstrated that mRNA of VEGF and its receptors in both healthy and diseased oviduct is expressed preferentially at the time and place where the amount of oviduct fluid is prominent. This supports the notion that VEGF may be a regulator of oviductal secretion. This thesis has consistently demonstrated a modulation pattern of flt-1 expression that is similar to its ligand VEGF in both physiological and pathological conditions. This suggests that flt-1 may be the main receptor responsible for the action of VEGF in the oviduct. As illustrated in both the in-vivo and in-vitro models, the expression of VEGF and flt-1 in the human oviduct is stimulated directly by gonadotropins without the influence of ovarian sex hormones. / Increased knowledge on the regulatory mechanisms of oviductal fluid formation, the first environment that human embryos are exposed to, will be valuable from the clinical management point of view. / Oviductal fluid is a complex mixture of plasma-derived constituents and proteins synthesized by the oviduct epithelium. It has been postulated that vascular endothelial growth factor (VEGF), a known permeability promoter, may be an important regulator of oviductal fluid secretion by stimulating vascular permeability and so serum transudation. However, little is known about the expression of VEGF in the human oviduct. This thesis investigated the modulation of VEGF and its receptors (flt-1 and KDR) in the healthy oviducts, from fertile women undergoing tubal sterilization for unwanted fertility or hysterectomy for benign gynecological conditions, as well as in the hydrosalpinges from sterile women undergoing salpingectomy before the treatment of in-vitro fertilization and embryo transfer. / Lam Po Mui. / Adviser: Christopher J. Haines. / Source: Dissertation Abstracts International, Volume: 73-01, Section: B, page: . / Thesis (M.D.)--Chinese University of Hong Kong, 2004. / Includes bibliographical references (leaves 147-179). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [201-] System requirements: Adobe Acrobat Reader. Available via World Wide Web.

published_or_final_version / Obstetrics and Gynaecology / Doctoral / Doctor of Philosophy

Thesis (Ed.D.)--Teachers College, Columbia University. / Typescript; issued also on microfilm. Sponsor: Hope Leichter. Dissertation Committee: Gilbert H. Shimmel. Includes bibliographical references.

Ajonuma Louis Chukwuemeka. / "March 2004." / Thesis (Ph.D.)--Chinese University of Hong Kong, 2004. / Includes bibliographical references (p. 215-238). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Mode of access: World Wide Web. / Abstracts in English and Chinese.