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Role of stem-like cells in breast cancer

Role of stem-like cells in breast cancer
Role of stem-like cells in breast cancer
Breast cancer is a leading cause of mortality in women worldwide, with a high incidence of tumour recurrence and metastasis, predominantly due to chemoresistance, key obstacles in the treatment of any cancer. Studies are emerging in support of the “cancer stem cells theory”, which postulates that a small subset of cancer cells is exclusively responsible for the initiation and malignant behaviour of a cancer that are highly tumorigenic, resistant to therapeutic regimes, and responsible for treatment failure and disease relapse. The emergence of cancer is also accompanied by specific metabolic alterations; in particular, enhanced aerobic glycolytic activity which leads to rapid tumour progression. Our current conventional therapies are based on eliminating differentiated tumours, whereas identification of the factors that lead to cancer stem-like cells (CSLCs) maintenance in the tumour population, could lead to the development of more effective therapeutics. Therefore, this thesis aimed to investigate the effect of modulating tumour cell metabolism, using a variety of metabolic inhibitors, on the maintenance of the stem cell population of breast cancer cells, to stop or slow down CSLCs growth. Additionally, this thesis aimed to study the expression levels of the main stem cell markers SOX2, OCT4, and its most homologous pseudogene (OCT4 PG1), in breast cancer following metabolic treatments and to investigate the effect of reducing the expression of these markers on the mammosphere forming ability of MCF-7 cells.

We developed a cell line model of glycolytic vs. glycolysis restricted cells by adapting cells to fructose in the absence of glucose so that cells could grow at normal rates without being glycolytic. We then proceeded to characterise the stem cell population of breast cancer cells using the mammosphere assay. Strikingly, this study demonstrated that MCF-7 cells are able to adapt to fructose conditions, proliferate in a programmed manner as glucose adapted cells, and significantly form more mammospheres than more glycolytic cells. This indicates that the CSLCs do not require a high rate of glycolysis to survive as long as they have sufficient substrate to grow. Moreover, it was found that SOX2 is more highly expressed in glycolysis restricted conditions and OCT4A is not present in breast cancer cell lines. OCT4 PG1 was expressed in some breast cancer cell lines (MCF-7), implying a possible role in carcinogenesis. Additionally, targeting different metabolic pathways found that the use of oxamate to inhibit glycolysis showed that glycolysis is not a critical metabolic pathway for CSLC activity in fructose adapted cells. In conclusion this work shows important links between glycolytic metabolism and pluripotency, and pluripotency related genes in breast cancer.
University of Southampton
Arvinrad, Pardis
91ce8f9a-bfc1-4b56-92ac-f8725cddffe5
Arvinrad, Pardis
91ce8f9a-bfc1-4b56-92ac-f8725cddffe5
Blaydes, Jeremy
e957f999-fd91-4f77-ad62-5b4ef069b15b

Arvinrad, Pardis (2016) Role of stem-like cells in breast cancer. University of Southampton, Doctoral Thesis, 231pp.

Record type: Thesis (Doctoral)

Abstract

Breast cancer is a leading cause of mortality in women worldwide, with a high incidence of tumour recurrence and metastasis, predominantly due to chemoresistance, key obstacles in the treatment of any cancer. Studies are emerging in support of the “cancer stem cells theory”, which postulates that a small subset of cancer cells is exclusively responsible for the initiation and malignant behaviour of a cancer that are highly tumorigenic, resistant to therapeutic regimes, and responsible for treatment failure and disease relapse. The emergence of cancer is also accompanied by specific metabolic alterations; in particular, enhanced aerobic glycolytic activity which leads to rapid tumour progression. Our current conventional therapies are based on eliminating differentiated tumours, whereas identification of the factors that lead to cancer stem-like cells (CSLCs) maintenance in the tumour population, could lead to the development of more effective therapeutics. Therefore, this thesis aimed to investigate the effect of modulating tumour cell metabolism, using a variety of metabolic inhibitors, on the maintenance of the stem cell population of breast cancer cells, to stop or slow down CSLCs growth. Additionally, this thesis aimed to study the expression levels of the main stem cell markers SOX2, OCT4, and its most homologous pseudogene (OCT4 PG1), in breast cancer following metabolic treatments and to investigate the effect of reducing the expression of these markers on the mammosphere forming ability of MCF-7 cells.

We developed a cell line model of glycolytic vs. glycolysis restricted cells by adapting cells to fructose in the absence of glucose so that cells could grow at normal rates without being glycolytic. We then proceeded to characterise the stem cell population of breast cancer cells using the mammosphere assay. Strikingly, this study demonstrated that MCF-7 cells are able to adapt to fructose conditions, proliferate in a programmed manner as glucose adapted cells, and significantly form more mammospheres than more glycolytic cells. This indicates that the CSLCs do not require a high rate of glycolysis to survive as long as they have sufficient substrate to grow. Moreover, it was found that SOX2 is more highly expressed in glycolysis restricted conditions and OCT4A is not present in breast cancer cell lines. OCT4 PG1 was expressed in some breast cancer cell lines (MCF-7), implying a possible role in carcinogenesis. Additionally, targeting different metabolic pathways found that the use of oxamate to inhibit glycolysis showed that glycolysis is not a critical metabolic pathway for CSLC activity in fructose adapted cells. In conclusion this work shows important links between glycolytic metabolism and pluripotency, and pluripotency related genes in breast cancer.

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THESIS FINAL Sep 2016
Available under License University of Southampton Thesis Licence.
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Published date: September 2016

Identifiers

Local EPrints ID: 434127
URI: http://eprints.soton.ac.uk/id/eprint/434127
PURE UUID: 2469b8c0-f8b4-4069-b63d-3eb6d74f2b62
ORCID for Jeremy Blaydes: ORCID iD orcid.org/0000-0001-8525-0209

Catalogue record

Date deposited: 13 Sep 2019 16:30
Last modified: 14 Sep 2019 00:37

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Contributors

Author: Pardis Arvinrad
Thesis advisor: Jeremy Blaydes ORCID iD

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