In this thesis, we studied some of the genetic and molecular alterations that accompany the tumorigenesis of mismatch repair (MMR) and MUTYH deficient colorectal cancers, with focus on immune... Show moreIn this thesis, we studied some of the genetic and molecular alterations that accompany the tumorigenesis of mismatch repair (MMR) and MUTYH deficient colorectal cancers, with focus on immune escape mechanisms. We discovered that loss of Human Leukocyte Antigen (HLA) class I expression was more frequent in those tumors than in the remaining spectrum of colorectal cancers (CRCs), and that distinct genetic mechanisms explained HLA class I abrogation in sporadic and hereditary mismatch repair deficient tumors. We then explored a potential association between the magnitude and quality of lymphocytic infiltration with the tumors__ HLA class I phenotypes and clinicopathological stages in a cohort of Lynch CRCs. Higher lymphocytic infiltration, particularly of cytotoxic lymphocytes, was observed in cancers presenting HLA class I defects and in tumors diagnosed at earlier stages, thus, supporting the role of the immune system in selecting immune evasive tumor traits and in counteracting cancer progression. Finally, we functionally characterized one of the most common genetic alterations that occur in MMR deficient CRCs. We demonstrated that TGFbeta signalling is active in these tumors and that TGFbeta activation occurs in a TGFBR2-dependent manner, despite the presence of truncating biallelic mutations in its gene in the majority of MMR deficient tumors. Show less
The focus of our research and this thesis was to investigate how statins are able to influence colorectal cancer formation and whether they might be used as a chemopreventive or adjuvant... Show moreThe focus of our research and this thesis was to investigate how statins are able to influence colorectal cancer formation and whether they might be used as a chemopreventive or adjuvant therapeutic agent in colorectal cancer. As we have shown, statins are able to influence colorectal cancer cells at different levels from the level of BMP receptor expression and receptor cycling, effects on the entire kinome in cancer cells, to epigenetic changes via its ability to alter gene promoter methylation. Our results suggest that statins could provide an interesting and favorable option for use in a chemopreventive or adjuvant setting. There are however aspects which have to be assessed before a drug is used for chemoprevention. The risk/benefit ratio should be assessed carefully, especially when administered to healthy individuals. Ideally, a chemopreventive agent should fulfill certain criteria. Most importantly, the drug must be effective and exhibit minimal side-effects. The safety profile of a drug and efficacy varies significantly between patients and is dependent on disease severity. Therefore, it is of great importance to critically assess the possible benefits of chemoprevention in comparison to the risk and inconvenience that could come with it. In the general population the lifetime risk of CRC is 5 % and the number needed to treat to prevent one CRC death will be very high. In patients at average risk, compliance in this asymptomatic cohort outside a study is likely to be low. The balance of risk versus benefit is more in favor of its use in high risk groups such as individuals especially susceptible to colorectal cancer because of environmental risk factors (diet high in animal protein and fat), patients with inflammatory bowel disease (IBD) and those with a hereditary predisposition to CRC. These include patients with Familial Adenomatous Polyposis (FAP), Lynch Syndrome, Hereditary Non Polyposis Colon Carcinoma (HNPCC) and patients with a previous history of colorectal or adenomatous polyps. However, effective chemoprevention within one high risk group does not mean that the same chemoprevention is suitable for all groups. This stems from and also illustrates the fact that CRC is not one disease but a heterogeneous group of diseases with different underlying molecular mechanisms. Statins have an excellent safety profile, have been use for decades and have a beneficial effect on cardiovascular disease risk even in healthy individuals. Next to this we have shown that the use of statins has strong protective effect on the development of colorectal cancer expressing SMAD4 and does not increase the risk of developing CRC in SMAD4 negative tumors. Taken together our results suggest that statins could present a very interesting and favorable agent for use in a chemopreventive or adjuvant setting in CRC. Show less
This thesis describes the research that investigated molecular biomarkers in defined groups of primary colorectal tumours to determine markers for site specific metastases.
This dissertation reports on the relation between the immune system, colorectal cancer and immunotherapy. In the first part, expression of HLA class I and expression of CXCL5 in colocectal cancer... Show moreThis dissertation reports on the relation between the immune system, colorectal cancer and immunotherapy. In the first part, expression of HLA class I and expression of CXCL5 in colocectal cancer was studied. Low expression of HLA class I in rectal tumors was associated with poor survival of rectal cancer patients. Low expression of CXCL5 in cancer cells was significantly associated with poor prognosis in a population of colorectal cancer patients and correlated with presence of intra-tumoral CD8+ T-cell infiltration. In the second part of this thesis we focused on induction of tumor specific T-cells. For immunotherapeutic purposes distinction should be made between microsatellite instable (MSI-H) and microsatellite stable (MSS) colorectal tumors, as MSI-H tumors express neo-antigens __foreign__ to the immune system while immunotherapy against MSS tumors depends on tumor associated __self__-antigens. We developed a methodology predicting immunogenic behavior of frameshift-mutated antigens present in MSI-H tumors that was based on accumulation and MHC class I presentation. This method can be used to develop cancer immunotherapy of patients at risk for MSI-H tumors. In the last two chapters we described safety and immunogenicity of a p53 synthetic long peptides vaccine combined with and without Interferon-alpha. Addition of IFN-_ to the p53-SLP_ vaccine significantly improved p53-specific after vaccination. Altogether this dissertation reports on the relation between the immune system, colorectal cancer and immunotherapy. This knowledge can be used to further optimize immunotherapeutic strategies to treat cancer patients. Show less
