Doctoral Degrees (Physiological Sciences)
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Browsing Doctoral Degrees (Physiological Sciences) by Author "De Waal, Greta Marie"
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- ItemThe link between chronic inflammation, hypercoagulation, and a bacterial presence in colorectal carcinogenesis(Stellenbosch : Stellenbosch University, 2021-04) De Waal, Greta Marie; Pretorius, Etheresia; De Villiers, Willem J. S.; Stellenbosch University. Faculty of Science. Dept. of Physiological Sciences.ENGLISH ABSTRACT: Colorectal cancer (CRC) leads to high rates of morbidity and mortality worldwide. CRC is a heterogeneous and highly complex disease, with factors such as genetic alterations, environmental risk factors, the gut microbiota, and inflammation contributing to the development and progression of colorectal tumours. A novel holistic approach was employed in this dissertation to investigate colorectal carcinogenesis, by analysing the systemic environment and local tumour environment of CRC patients. A close link exists between persistent infections, chronic (systemic) inflammation, and colorectal carcinogenesis. There is also an intricate relationship between gut dysbiosis and a pro- inflammatory profile in CRC patients. Alterations in the composition of the gut microbiota can contribute to the development of a dysfunctional gut barrier, thereby facilitating the translocation of bacteria and their highly potent inflammagenic molecules (specifically the presence of circulating lipopolysaccharide (LPS)). Such leaky gut conditions can promote systemic inflammation, of which a hallmark is increased hypercoagulability. Importantly, chronic inflammation and an activated (pathological) coagulation system are implicated in tumorigenesis. It was hypothesised that the presence of Helicobacter pylori, Escherichia coli, LPS, serum amyloid A (SAA), as well as structural changes in proteins are increased inside CRC tumour cells and/or their microenvironment, compared to control tissues. Furthermore, that circulating levels of LPS are elevated in CRC patients, compared to healthy subjects; and that the increased presence of circulating LPS and inflammatory molecules such as SAA (systemic inflammation) contributes to a hypercoagulable state and promotes hematological dysfunction in CRC patients. In this dissertation it was shown that there is an intratumour bacterial presence in CRC patients, together with significantly elevated levels of the bacterial wall component LPS in their circulation, compared to controls. It was also demonstrated that these patients have a pro-inflammatory profile, accompanied by coagulopathies. Moreover, it was found that structural protein changes are increased in CRC tumour tissues. The discovery of additional (novel) biomarkers for CRC screening, together with the development and employment of novel methods for the early detection of CRC risk, represent a growing research field and are crucial for the application of a true “personalized medicine” approach that can enable improved early CRC detection, diagnosis, and prognosis. Importantly, blood-based screening tools are an emerging research area of interest for CRC screening. Early detection of the presence of dysregulated circulating inflammatory markers and early diagnosis of an activated coagulation system, together with the detection of bacterial components in circulation and also in the local tumour environment, could be important, and may, in conjunction with modulation of the gut microbiota, serve as potential therapeutic targets. A holistic view enables us to have a better overall understanding of the link between chronic inflammation, hypercoagulation, and a bacterial presence in colorectal carcinogenesis. The hypothesis of this dissertation was supported in such a way that the findings can be applied in a clinical setting. The way forward is therefore to apply these (clinically relevant) novel research findings in practice, in order to aid in the early identification of individuals with an increased risk for CRC.