The Effects of the Female Reproductive Hormones on Ovarian Cancer Initiation and Progression in a Transgenic Mouse Model of the Disease
Ovarian cancer is thought to be derived from the ovarian surface epithelium (OSE), but it is often diagnosed during the late stages and therefore the events that contribute to the initiation and progression of ovarian cancer are poorly defined. Epidemiological studies have indicated an association...
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Université d'Ottawa / University of Ottawa
2011
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Online Access: | http://hdl.handle.net/10393/19939 http://dx.doi.org/10.20381/ruor-5772 |
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ndltd-uottawa.ca-oai-ruor.uottawa.ca-10393-199392018-01-05T19:00:57Z The Effects of the Female Reproductive Hormones on Ovarian Cancer Initiation and Progression in a Transgenic Mouse Model of the Disease Laviolette, Laura Vanderhyden, Barbara ovarian cancer mouse model 17β-estradiol progesterone ovarian surface epithelium menopause VCD follicle stimulating hormone luteinizing hormone Ovarian cancer is thought to be derived from the ovarian surface epithelium (OSE), but it is often diagnosed during the late stages and therefore the events that contribute to the initiation and progression of ovarian cancer are poorly defined. Epidemiological studies have indicated an association between the female reproductive hormones and ovarian cancer etiology, but the direct effects of 17β-estradiol (E2), progesterone (P4), luteinizing hormone (LH) and follicle stimulating hormone (FSH) on disease pathophysiology are not well understood. A novel transgenic mouse model of ovarian cancer was generated that utilized the Cre/loxP system to inducibly express the oncogene SV40 large and small T-Antigen in the OSE. The tgCAG-LS-TAg mice developed poorly differentiated ovarian tumours with metastasis and ascites throughout the peritoneal space. Although P4 had no effect; E2 significantly accelerated disease progression in tgCAG-LS-TAg mice. The early onset of ovarian cancer was likely mediated by E2’s ability to increase the areas of putative preneoplastic lesions in the OSE. E2 also significantly decreased survival time in ovarian cancer cell xenografts. Microarray analysis of the tumours revealed that E2 mainly affects genes involved in angiogenesis and cellular differentiation, proliferation, and migration. These results suggest that E2 acts on the tumour microenvironment in addition to its direct effects on OSE and ovarian cancer cells. In order to examine the role of the gonadotropins in ovarian cancer progression, the tgCAG-LS-TAg mice were treated with 4-vinylcyclohexene-diepoxide (VCD) to induce menopause. Menopause slowed the progression of ovarian cancer due to a change in the histological subtype from poorly differentiated tumours to Sertoli tumours. Using a transgenic mouse model, it was shown that E2 accelerated ovarian cancer progression, while P4 had little effect on the disease. Menopause (elevated levels of LH and FSH) altered the histological subtype of the ovarian tumours in the tgCAG-LS-TAg mouse model. These results emphasize the importance of generating animal models to accurately recapitulate human disease and utilizing these models to develop novel prevention and treatment strategies for women with ovarian cancer. 2011-05-03T16:45:01Z 2012-05-03T07:00:07Z 2011 2011 Thesis http://hdl.handle.net/10393/19939 http://dx.doi.org/10.20381/ruor-5772 en Université d'Ottawa / University of Ottawa |
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language |
en |
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ovarian cancer mouse model 17β-estradiol progesterone ovarian surface epithelium menopause VCD follicle stimulating hormone luteinizing hormone |
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ovarian cancer mouse model 17β-estradiol progesterone ovarian surface epithelium menopause VCD follicle stimulating hormone luteinizing hormone Laviolette, Laura The Effects of the Female Reproductive Hormones on Ovarian Cancer Initiation and Progression in a Transgenic Mouse Model of the Disease |
description |
Ovarian cancer is thought to be derived from the ovarian surface epithelium (OSE), but it is often diagnosed during the late stages and therefore the events that contribute to the initiation and progression of ovarian cancer are poorly defined. Epidemiological studies have indicated an association between the female reproductive hormones and ovarian cancer etiology, but the direct effects of 17β-estradiol (E2), progesterone (P4), luteinizing hormone (LH) and follicle stimulating hormone (FSH) on disease pathophysiology are not well understood.
A novel transgenic mouse model of ovarian cancer was generated that utilized the Cre/loxP system to inducibly express the oncogene SV40 large and small T-Antigen in the OSE. The tgCAG-LS-TAg mice developed poorly differentiated ovarian tumours with metastasis and ascites throughout the peritoneal space. Although P4 had no effect; E2 significantly accelerated disease progression in tgCAG-LS-TAg mice. The early onset of ovarian cancer was likely mediated by E2’s ability to increase the areas of putative preneoplastic lesions in the OSE.
E2 also significantly decreased survival time in ovarian cancer cell xenografts. Microarray analysis of the tumours revealed that E2 mainly affects genes involved in angiogenesis and cellular differentiation, proliferation, and migration. These results suggest that E2 acts on the tumour microenvironment in addition to its direct effects on OSE and ovarian cancer cells.
In order to examine the role of the gonadotropins in ovarian cancer progression, the tgCAG-LS-TAg mice were treated with 4-vinylcyclohexene-diepoxide (VCD) to induce menopause. Menopause slowed the progression of ovarian cancer due to a change in the histological subtype from poorly differentiated tumours to Sertoli tumours.
Using a transgenic mouse model, it was shown that E2 accelerated ovarian cancer progression, while P4 had little effect on the disease. Menopause (elevated levels of LH and FSH) altered the histological subtype of the ovarian tumours in the tgCAG-LS-TAg mouse model. These results emphasize the importance of generating animal models to accurately recapitulate human disease and utilizing these models to develop novel prevention and treatment strategies for women with ovarian cancer. |
author2 |
Vanderhyden, Barbara |
author_facet |
Vanderhyden, Barbara Laviolette, Laura |
author |
Laviolette, Laura |
author_sort |
Laviolette, Laura |
title |
The Effects of the Female Reproductive Hormones on Ovarian Cancer Initiation and Progression in a Transgenic Mouse Model of the Disease |
title_short |
The Effects of the Female Reproductive Hormones on Ovarian Cancer Initiation and Progression in a Transgenic Mouse Model of the Disease |
title_full |
The Effects of the Female Reproductive Hormones on Ovarian Cancer Initiation and Progression in a Transgenic Mouse Model of the Disease |
title_fullStr |
The Effects of the Female Reproductive Hormones on Ovarian Cancer Initiation and Progression in a Transgenic Mouse Model of the Disease |
title_full_unstemmed |
The Effects of the Female Reproductive Hormones on Ovarian Cancer Initiation and Progression in a Transgenic Mouse Model of the Disease |
title_sort |
effects of the female reproductive hormones on ovarian cancer initiation and progression in a transgenic mouse model of the disease |
publisher |
Université d'Ottawa / University of Ottawa |
publishDate |
2011 |
url |
http://hdl.handle.net/10393/19939 http://dx.doi.org/10.20381/ruor-5772 |
work_keys_str_mv |
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