Cancer immunology and inflammation

Postgraduate Thesis uoadl:2814310 1099 Read counter

Unit:
Κατεύθυνση Εφαρμογές της Βιολογίας στην Ιατρική
Library of the School of Science
Deposit date:
2018-10-25
Year:
2018
Author:
Theodorou Sofia
Supervisors info:
Αθανάσιος Κοτσίνας, Επίκουρος Καθηγητής, Τομέας Ιστολογίας και Εμβρυολογίας, Ιατρική Σχολή, ΕΚΠΑ
Original Title:
Ανοσολογία και φλεγμονή στον καρκίνο
Languages:
Greek
Translated title:
Cancer immunology and inflammation
Summary:
Cancer is a potentially lethal disease, characterized by high prevalence. Carginogenesis is a multistep process in which complex pathogenetic mechanisms are involved, including genetic and epigenetic aberrations and an interplay between genetic and environmental factors. The cancer cells acquire some capacities; known as the hallmarks of cancer: a) sustaining proliferative signaling, b) evading growth supressors, c) avoiding immune destruction, d) enabling replicative immortality, e) tumor-promoting inflammation, f) activating invasion and metastasis, g) inducing angiogenesis, h) genomic instability, i) resisting cell death and j) deregulating cellular energetics.
Inflammation is the biological response to harmful stimuli or loss of cellular and tissue homeostasis. Chronic infection and inflammation are correlated with a high risk of cancer development. IBD is a major example, since was shown to be correlated with the development of colorectal carcinomas. Almost 20% of cancer incidents worldwide are associated with the existence of a persistent infection or chronic inflammation. The role of immunity and inflammation is crucial, since inflammation can contribute to the initiation and progression of carcinogenesis by supplying the tumor microenvironment with growth, survival and angiogenetic factors and also ROS, thus leading to genomic instability. However immunosurveillance contributes to an early detection and elimination of transformed cancer cells, during the initiation or the metastatic stage.
Homeostasis of the gut microflora is crucial to be maintained, since changes in the microbiome and the domination of pathogen microorganisms can lead to intestinal inflammation through PRRs activation or through endocytosis or adhesion or toxin secretion. There are three types of toxins known: a)cytolethal distending toxins (CDTs), b) typhoid toxin and c) colibactin. The first two types create double-strand DNA breaks and thus activate the DNA damage response mechanism. If the DNA lesions cannot be repaired, cancer transformation is possible to take place.
Fueled by the latest scientific data regarding the typhoid toxin, we studied the effect of administrating Salmonella Typhimurium strains that can express (TT) or not (Delta) the active typhoid toxin to transgenic mice with the following genotypes: WT (wild type), TP53 heteroxygous (+/-), TP53 KO (knockout), ATM heterozygous (+/-) and ATM KO. Our purpose is to clarify the effect of typhoid toxin on the intestinal homeostasis and especially in mice where ATM and p53 are fully or partially missing.
We conducted histological and immunohistochemical analysis, that lead to the following conclusions: inflammation of a lower severity and lower levels of the γΗ2ΑΧ marker were observed in the intestines of the mice that received the active toxin (TT) in contrast to the mice that received the inactive form of the toxin (Delta). By examining p65/NF-κΒ, which is the main regulator of inflammation, we observed statistically significant lower levels of the marker in mice that the inactive toxin was administered comparing to those that received the active form. Furthermore, the examination of two markers regarding T and B lymphocytes brought us to the conclusion that typhoid toxin has an immune modulator role.
Based on the above, the presence of the typhoid toxin disrupts the intestinal homeostasis. However, further research is required in order to elucidate the underlying mechanisms.
Main subject category:
Science
Keywords:
cancer, immunology, inflammation, chronic inflammation, toxins, genotoxins, microbiome
Index:
No
Number of index pages:
0
Contains images:
Yes
Number of references:
82
Number of pages:
103
ΔΙΟΡΘΩΜΕΝΗ ΔΙΠΛΩΜΑΤΙΚΗ ΕΡΓΑΣΙΑ-ΑΝΟΣΟΛΟΓΙΑ ΚΑΙ ΦΛΕΓΜΟΝΗ ΣΤΟΝ ΚΑΡΚΙΝΟ - ΘΕΟΔΩΡΟΥ ΣΟΦΙΑ ΑΜ 41610.pdf (6 MB) Open in new window