The link between chronic inflammation, hypercoagulation, and a bacterial presence in colorectal carcinogenesis

Date
2021-04
Journal Title
Journal ISSN
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Publisher
Stellenbosch : Stellenbosch University
Abstract
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.
AFRIKAANSE OPSOMMING: Kolorektale kanker (KRK) raak ‘n groot aantal mense en lei tot ‘n hoë sterftekoers wêreldwyd. KRK is ‘n hoogs komplekse siekte met verskeie faktore, insluitend genetiese veranderinge, omgewingsrisikofaktore, die intestinale mikrobiota en inflammasie, wat bydra tot die ontstaan en ontwikkeling van kolorektale tumors. ‘n Oorspronklike en holistiese benadering is in hierdie proefskrif toegepas om kolorektale karsinogenese te ondersoek deur die sistemiese omgewing en die lokale tumoromgewing van KRK-pasiënte te analiseer. Daar is ‘n noue verbintenis tussen aanhoudende infeksies, kroniese (sistemiese) inflammasie en kolorektale karsinogenese. Daar is ook ‘n ingekwikkelde verhouding tussen intestinale disbiose en ‘n pro-inflammatoriese profiel in KRK- pasiënte. Veranderinge wat plaasvind in die samestelling van die intestinale mikrobiota kan bydra tot die ontwikkeling van ‘n abnormale intesitinale versperring, wat dan die beweging van bakterieë en bakteriële komponente fasiliteer en inflammatoriese reaksies kan ontlok (spesifiek die teenwoordigheid van lipopolisakkaried (LPS) in bloedsirkulasie). Lekkende of deurlaatbare dermtoestande kan sistemiese inflammasie stimuleer, waarvan oormatige bloedklonting (hiperkoagulasie) ‘n bekende kenmerk is. Kroniese inflammasie en geaktiveerde (patologiese) bloedklonting word met tumor-ontwikkeling verbind. Die hipotese was dat die teenwoordigheid van Helicobacter pylori, Escherichia coli, LPS, “serum amyloid A (SAA)” en ook strukturele proteïenveranderinge verhoog is binne KRK-tumorselle en/of hul mikro-omgewing, in vergelyking met kontroleweefsels. Verder, dat die vlakke van LPS in die bloedsirkulasie van KRK-pasiënte verhoog is, in vergelyking met dié van gesonde individue; en dat die verhoogde vlakke van LPS en inflammatoriese molekules soos SAA (sistemiese inflammasie) in bloedsirkulasie bydra tot hiperkoagulasie en ook abnormale bloedklonting in KRK-pasiënte vererger. In hierdie proefskrif is daarop gewys dat daar ‘n bakteriële teenwoordigheid binne die tumors van KRK-pasiënte is, asook, in vergelyking met kontroles, beduidende verhoogde vlakke van die bakteriële wandkomponent LPS in hul bloedsirkulasie. Daar is ook aangedui dat hierdie pasiënte ‘n pro-inflammatoriese profiel het, wat met abnormale bloedklonting gepaard gaan. Verder is daar ook bevind dat strukturele proteïenveranderinge in KRK-tumorweefsels verhoog is. Die ontdekking van nuwe biomerkers vir KRK-sifting, saam met die ontwikkeling en toepassing van nuwe metodes om KRK-risiko vroeg te kan opspoor, verteenwoordig ‘n groeiende navorsingsgebied. Dit is noodsaaklik vir die toepassing van ‘n ware persoonsgerigte gesondheidsbenadering wat die vroeë opsporing, diagnose en prognose van KRK kan verbeter. Bloedgebaseerde siftingstegnieke is eweneens ‘n ontluikende navorsingsgebied wat aandag trek rakende KRK-sifting. Die vroeë opsporing van dereguleerde sirkulerende inflammatoriese merkers en die vroeë diagnose van geaktiveerde bloedklonting, saam met die opsporing van bakteriële komponente in sowel die bloedsirkulasie as die lokale tumoromgewing, kan belangrik wees en mag in samehang met die modulering van die intestinale mikrobiota as potensiële terapeutiese teikens dien. ‘n Holistiese benadering maak dit moontlik om ‘n beter algehele begrip van die verband tussen kroniese inflammasie, hiperkoagulasie en ‘n bakteriële teenwoordigheid in kolorektale karsinogenese te verkry. Die hipotese van hierdie proefskrif is op sodanige wyse gestaaf dat die bevindinge in ‘n kliniese opset toegepas kan word. Die benadering vir die toekoms is dus om hierdie nuwe en klinies-relevante navorsingsbevindinge in die praktyk toe te pas, sodat die vroeë identifisering van individue met ‘n verhoogde KRK-risiko bevorder kan word.
Description
Thesis (PhD)--Stellenbosch University, 2021.
Keywords
Colorectal cancer, Inflammation, Hypercoagulation, Bacteria, Carcinogenesis -- Environmental aspects, Tumors cells, Inflammation -- Mediators, UCTD
Citation