A Master's thesis.
Master (thesis) (master)
Differential Gene-expression analysis of 6 immunogenes in colon cancer
Université de Lausanne, Faculté de biologie et médecine
Number of pages
Over decades, development of tumor was explained as a succession of genetic modifications leading to an ultimate loss of control and spreading of altered cells or group of cells. However, recent studies renewed interest in cancer microenvironment in general and immune-surveillance in particular. It is known that colorectal cancers (CRC) induc- ing a potent lymphocytic reaction are associated with improved long-term prognosis. Interestingly, this increase in survival seems independent of patient characteristics or other related molecular variables including KRAS mutation or the number of tumor con- taining lymph nodes. Several studies showed that analysis of the location, density and functional orientation of immune cells in colorectal cancers was able to define sub- groups of patients with similar outcome (1). These studies showed that these immuno- logical data are better predictor of patient survival than the TNM-classification currently used to stage colorectal cancer (2). The activation of the immune system is triggered by a myriad of cytokines, leading to the regulation of numerous genes related to the adap- tive immunity, inflammation and immunosuppression. In colorectal tumours the gene expression profiles of 18 immunogenes were analysed (3). These data showed a domi- nant cluster of co-modulated genes for adaptive immunity and two clusters of genes en- coding mediators of inflammation and immunosuppression. An inverse correlation was found between the mRNA level of genes involved in the T helpers 1 (Th1) immunity and recurrence of 75 CRC p<0.0001 (1). A strong correlation was achieved by interferon regulatory factor 1 (IRF-1), IFN-γ, CD8a and granzyme B. Patients with a homogenously increased expression of these genes had the best prognosis. IRF-1 is a transcription fac- tor promoting the regulation of IFN-γ, a major cytokine involved in the activation of the adaptive immunity (4). The protein encoded by granzyme B plays a crucial role in the induction of cell apoptosis induced by the T lymphocytes and natural killer cells. CD8 antigen is a glycoprotein on the cell surface found on cytotoxic T lymphocytes whose function is to mediate cell interactions. In fact, CD8 antigen acts as a co-receptor, recog- nized by the T-cell receptor. CD8a interacts with HLA-A stabilizing interactions between the T-cell receptor on cytotoxic (CD8+) T-lymphocytes and the Class I MHC. IL-15 in- duces cell activation and proliferation of innate immunity, that is of natural killer cells and regulates memory T-cells by co-acting with IL-2 (5,6). Recent data suggests that a decreased expression of IL-15 is linked to a higher risk of recurrence and a reduced patient survival, underlining the role of this cytokine in the context of colorectal cancers (7)
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