Influence of cancer associated microbiome on volatile organic compound production in oesophago-gastric adenocarcinoma
File(s)
Author(s)
Adam, Mina Samy Edward
Type
Thesis
Abstract
Oesophago-gastric cancer is a significant health problem with poor prognosis in Western countries. This is due to a paucity of alarm symptoms in early stages of the disease resulting in late clinical presentation and associated delays in initiation of treatment. The development of non-invasive breath tests using exhaled Volatile Organic compounds (VOCs) to determine oesophago-gastric cancer risk would help facilitate earlier diagnosis and potentially improve patient survival. Whilst many of the biochemical pathways relating to the origin of these VOCs within humans are as yet unknown, it is postulated that that specific VOCs are produced directly by cancer tissues. Contributions from other endogenous sources including the intestinal microbiome and healthy tissues within the intestinal tract as well as other organ systems. The aim of this thesis was to understand the interaction between the upper gastrointestinal microbiome and VOC production in patients with oesophago-gastric cancer and to explore how this onco-microbial axis can be exploited to augment VOC production.
The production of cancer associated VOCs (fatty acids and phenol) were investigated by analysing the ex vivo headspace above un-derivatised tissue samples as well as in vivo mixed breath, isolated bronchial breath and gastric endoluminal air. Increased concentrations of these VOCs were detected in the headspace of cancer tissue samples as well as isolated endoluminal air adjacent to tumours. Findings therefore implicate that the tumour and its local environment are the likely source of upregulated VOCs in oesophago-gastric cancer. The relative contribution of the tumour associated microbiome remains unknown.
16S RNA sequencing analysis for 185 oesophago-gastric tissue samples from cancer and control subjects were performed in order to assess the microbial diversity. Results revealed higher abundance of Firmicutes (e.g. Streptococcus salivarius, Escherichia coli and Streptococcus anginosus) in oesophago-gastric cancer samples compared to controls. The headspace of in vitro and patient derived (ex vivo) cultures of specific targeted bacteria was subsequently found to contain similar VOCs as those previously detected in oesophago-gastric cancer.
To increase the sensitivity of breath testing, further work was performed to augment the diagnostic response using simple metabolic substrates (sugars, proteins, lipids). When added to in vitro cultures of cancer-associated bacteria, these nutrients resulted in upregulated VOC production. Oesophago-gastric cancer patients who were given the same substrates orally were found to have a transient rise in the same VOCs that was greater than observed in healthy controls.
This thesis provides new insight into the biological origin of VOC production in oesophago-gastric cancer. Experiments linking the cancer-associated microbiome, exogenous substrates to upregulated VOC production in cancer patients offers the potential for a future augmented breath test for this disease. The augmented breath test is expected to increase earlier cancer detection leading to improvement in overall survival.
The production of cancer associated VOCs (fatty acids and phenol) were investigated by analysing the ex vivo headspace above un-derivatised tissue samples as well as in vivo mixed breath, isolated bronchial breath and gastric endoluminal air. Increased concentrations of these VOCs were detected in the headspace of cancer tissue samples as well as isolated endoluminal air adjacent to tumours. Findings therefore implicate that the tumour and its local environment are the likely source of upregulated VOCs in oesophago-gastric cancer. The relative contribution of the tumour associated microbiome remains unknown.
16S RNA sequencing analysis for 185 oesophago-gastric tissue samples from cancer and control subjects were performed in order to assess the microbial diversity. Results revealed higher abundance of Firmicutes (e.g. Streptococcus salivarius, Escherichia coli and Streptococcus anginosus) in oesophago-gastric cancer samples compared to controls. The headspace of in vitro and patient derived (ex vivo) cultures of specific targeted bacteria was subsequently found to contain similar VOCs as those previously detected in oesophago-gastric cancer.
To increase the sensitivity of breath testing, further work was performed to augment the diagnostic response using simple metabolic substrates (sugars, proteins, lipids). When added to in vitro cultures of cancer-associated bacteria, these nutrients resulted in upregulated VOC production. Oesophago-gastric cancer patients who were given the same substrates orally were found to have a transient rise in the same VOCs that was greater than observed in healthy controls.
This thesis provides new insight into the biological origin of VOC production in oesophago-gastric cancer. Experiments linking the cancer-associated microbiome, exogenous substrates to upregulated VOC production in cancer patients offers the potential for a future augmented breath test for this disease. The augmented breath test is expected to increase earlier cancer detection leading to improvement in overall survival.
Version
Open Access
Date Issued
2019-08
Date Awarded
2019-12
Copyright Statement
Creative Commons Attribution NonCommercial Licence
License URL
Advisor
Hanna, George
Marchesi, Julian
Kumar, Sacheen
Publisher Department
Department of Surgery & Cancer
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)