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Systems Biology of HIF Metabolism in Cancer
[Thesis]. Manchester, UK: The University of Manchester; 2012.
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Abstract
AbstractThe University of ManchesterFaculty of Engineering and Physical SciencesAbstract of thesis entitled ‘Systems Biology of HIF Metabolism in Cancer’Submitted by Emily Grace Armitage for the degree of Doctor of Philosophy, September 2012Cancer is one of the most devastating human diseases that cause a vast number of mortalities worldwide each year. Cancer research is one of the largest fields in the life sciences and despite many astounding breakthroughs and contributions over the past few decades, there is still a considerable amount to unveil on the function of cancer that would improve diagnostics, prognostics and therapy. Since cancer is known to involve a wide range of processes, applying methods to study it from a systems perspective could reveal new properties of cancer. Systems biology is becoming an increasingly popular tool in the life sciences. The approach has been applied to many biological and biomedical analyses drawing upon recent advancements in technology that make high throughput analyses of samples and computational modelling possible. In this thesis, the effect of hypoxia inducible factor-1 (HIF-1) on cancer metabolism, the entity considered most closely related to phenotype has been investigated. This transcription factor is known to regulate a multitude of genes and proteins to promote survival in a low oxygen environment that is prevalent in solid tumours. However its effect on the metabolome is less well characterised. By revealing the effect of HIF-1 on the metabolome as a system it is hoped that phenotypic signatures, key metabolic pathways indicative of cancer function and potential targets for future cancer therapy, can be revealed.The system has been studied using two cell models: mouse hepatocellular carcinoma and human colon carcinoma, whereby metabolism has been profiled using a range of analytical platforms. In each model, wild type cells have been compared to cells deficient in HIF-1 to reveal its effect on cellular metabolism. Gas chromatography mass spectrometry (GC MS) and ultra high performance liquid chromatography - mass spectrometry (UHPLC MS) have been employed for metabolic profiling of cells exposed to a range of oxygen conditions. Additionally, time-of-flight secondary ion mass spectrometry (ToF SIMS) has been employed for imaging mass spectrometric analysis of multicellular tumour spheroids cultured from wild type cells and cells with dysfunctional HIF-1 to represent small initiating tumours. Using these techniques in metabolic profiling it has been possible to reveal metabolites associated with the effect of oxygen and HIF-1 on cancer metabolism along with key pathways and hubs that could be targeted in future therapy. Using imaging mass spectrometry it has been possible to localise metabolites in situ revealing how tumour structure relates to function. Finally, a novel approach to consider how metabolites are correlated with one another in the response to oxygen level or presence or absence of functional HIF-1 has been undertaken to better understand the systems properties of cancer metabolism. Metabolites found to be differently correlated with respect to oxygen and/or HIF-1 have been mapped onto a human metabolic network to determine their network-based origins. This allowed the simulation of sub-networks of metabolism most affected by oxygen and HIF-1, highlighting the key mechanisms in HIF 1 mediated cancer cell survival.
Layman's Abstract
Lay AbstractThe University of ManchesterFaculty of Engineering and Physical SciencesLay Abstract of thesis entitled ‘Systems Biology of HIF Metabolism in Cancer’Submitted by Emily Grace Armitage for the degree of Doctor of Philosophy, September 2012Cancer is one of the most devastating human diseases that cause a vast number of mortalities worldwide each year. Cancer research is one of the largest fields in the life sciences and despite many astounding breakthroughs and contributions over the past few decades, there is still a considerable amount to unveil on the function of cancer that would improve diagnostics, prognostics and therapy. Since cancer is known to involve a wide range of processes, applying methods to study it as a whole system could reveal new properties of cancer. Systems biology is becoming an increasingly popular tool in the life sciences. The approach has been applied to many biological and biomedical analyses drawing upon recent advancements in technology. When tumours grow, their oxygen supply becomes scarce and they need to employ mechanisms to overcome this for survival. In this thesis, tumour metabolism has been investigated with particular emphasis on how tumours respond to low oxygen. This has involved the analysis small molecules using state of the art techniques to determine which molecules are caused by and appear to promote survival in tumour cells in low oxygen. These molecules have also been imaged in cross sections of tumours to see where they occur and to hypothesise the function of these molecules based on their position with respect to oxygen availability. Using the data from each analysis it has been possible to link together knowledge about the molecules revealed to consider how tumours survive in low oxygen as a whole system.