Colorectal cancer (CRC) is often treated with chemotherapy. However, it is well known that treatment with chemotherapy comes with challenges, such as (severe) adverse events leading to loss of... Show moreColorectal cancer (CRC) is often treated with chemotherapy. However, it is well known that treatment with chemotherapy comes with challenges, such as (severe) adverse events leading to loss of quality of life, treatment discontinuation and sometimes even death. Moreover, chances for curation in the metastatic setting are low. Therefore, a large window of opportunity to improve both safety as well as efficacy of chemotherapeutic treatment for the individual patient exists. A possible approach to improve chemotherapeutic treatment for CRC patients could be the discovery, validation and implementation of new genetic biomarkers. The use of genetic biomarkers allows to identify patients that are at higher risk for severe adverse drug events and to select patients which will benefit the most from chemotherapy. The aim of this thesis was therefore to improve the safety and efficacy of chemotherapeutic drugs in patients with colorectal cancer by individualising drug dosing and choice of drug based on germline genetic biomarkers. The described studies in this thesis brought us a few steps closer to safe and effective use of chemotherapeutic drugs in the individual colorectal cancer patient. Irinotecan should no longer be administered without a UGT1A1 genotype test and a start has been made towards personalised medicine for colorectal cancer patients with peritoneal metastases. Show less
Glycosylation is a widely occurring and complex modification found on lipids and proteins and is involved in the recognition, signaling and interaction events within the cell and between cells.... Show moreGlycosylation is a widely occurring and complex modification found on lipids and proteins and is involved in the recognition, signaling and interaction events within the cell and between cells. These events based on glycan structures result in adhesion, cell-matrix interaction and immune recognition. Alterations in the glycomic profile are considered a hallmark of various diseases, including cancer where it contributes to the development and progression of cancer, affecting cell-cell communication, cell-matrix interactions, tumor angiogenesis, invasion and metastasis. These functions are governed by different glycans and their terminal structures. In order to further explore these structures with regard to their potential as biomarkers and specific targets for diagnostic applications and therapeutical strategies for various diseases, in-depth glycomic analysis is needed. It is further noted that aberrant glycosylation not only results from the altered expression of glycosyltransferases (GTs) but also from the changed activity of GTs and glycosidases as well as the availability and abundance of sugar nucleotide donors. The aim of the research described in this thesis was to explore the glycomic signatures of colorectal cancer (CRC) in cell lines and tissues as well as of acute myeloid leukemia (AML) cell lines. Show less
Colorectal tumours with high stromal content have a poor prognosis. In part 1, I investigated, at the protein and gene expression levels, the composition of these tumours in comparison to stroma... Show moreColorectal tumours with high stromal content have a poor prognosis. In part 1, I investigated, at the protein and gene expression levels, the composition of these tumours in comparison to stroma-low tumours. In part 2, KRAS mutant colorectal cancer cell lines had a different metabolism compared to KRAS wild type after inhibition of mTORC1. This may contribute to therapeutic resistance. 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.
Colorectal cancer (CRC) is the second leading cause of cancer death in the Netherlands and the fourth worldwide. Matrix metalloproteinases (MMPs) are involved in the process of colorectal cancer... Show moreColorectal cancer (CRC) is the second leading cause of cancer death in the Netherlands and the fourth worldwide. Matrix metalloproteinases (MMPs) are involved in the process of colorectal cancer development and progression. MMPs are capable of degrading the extracellular matrix components of the intestinal basement membrane and facilitate invasion into the deeper layers of the bowel wall, lymph nodes and/or blood vessels. Furthermore, they are implicated in several processes in the microenvironment of colorectal cancer, like angiogenesis, cell death and inflammation. In this thesis, the focus is on the clinical impact of matrix metalloproteinases (MMPs) in the different stages of colorectal cancer development and metastasis. MMP-7, -8 and -9 were shown to be involved in the early stages of colorectal cancer development, whereas MMP-2 levels were only increased in cancer tissue but not in precancerous lesions. Furthermore, MMP-2, MMP-7 and MMP-9 were identified as predictors of outcome in patients with colorectal carcinoma, both at genetic (SNP) and protein level. The increased knowledge of the role of MMPs in the various stages of CRC might contribute to further development of specific anti-MMP therapies in the future. Show less
Colorectal cancer is one of the most common malignancies in the world. A family history of colon cancer has been shown to increase an individual’s risk of developing the disease. Approximately 2-3%... Show moreColorectal cancer is one of the most common malignancies in the world. A family history of colon cancer has been shown to increase an individual’s risk of developing the disease. Approximately 2-3% of all colorectal cancers occur in the setting of a well described autosomal dominant inherited syndrome: The Lynch syndrome. It is essential to identify individuals at increased risk to offer adequate surveillance programs to prevent the development of tumors or recognize them at an early stage. This thesis gives a laboratory workup of suspected Lynch syndrome, including analysis of tumor tissue by microsatellite instability analysis and immunohistochemistry, and germline DNA analysis. Several aspects of surveillance in Lynch syndrome are described. The appropriate screening interval is discussed and the effect on mortality because of surveillance is shown. Further, we sought to establish whether individuals from dominant families without mismatch repair deficiency are also at increased risk by examining the incidence of advanced neoplasia during surveillance. Finally, the prevalence of the frequency of a positive family history for CRC, within a random cohort among the Dutch population is presented and also the prevalence of adenomas among young individuals at average risk for colorectal cancer is shown. Show less
