Christian Doppler Laboratory
for Molecular Cancer Chemoprevention
 

 

RESEARCH PROJECTS

1. CHRISTIAN DOPPLER LABORATORY
for Molecular Cancer Chemoprevention:

Colorectal cancer (CRC) is the second leading cause of cancer death in the Western world. Progress has been made in understanding the molecular mechanisms of colon carcinogenesis (Wnt pathway, microsatellite instability, CpG-island-methylator phenotype) and in the variety of therapeutic modalities. However, advanced (metastatic) disease is still associated with short life expectancy and excessive health care costs. Prevention of cancer is a promising alternative strategy to safe lives and health care resources.

Epidemiological and interventional studies showed that salicylate-derivatives (aspirin, mesalazine), some non-steroidal anti-inflammatory drugs (NSAIDs), COX-2 inhibitors, or the naturally occurring phenolic acid derivative curcumin, protect from adenoma or CRC development. From a mechanistic point of view, these compounds seem to interfere with different pathways of colon carcinogenesis (e.g. aspirin is active in preventing sporadic CRC and adenoma recurrence, whereas mesalazine is particularly efficient in preventing inflammation-associated CRC). In vitro, mesalazine decreases the proliferation of colorectal epithelial cells, activates replication checkpoints, and reduces the rate of replication errors. In contrast, aspirin restrains cell proliferation by inducing a p21Waf1/Cip1- and ATM-dependent G1-arrest and p53-dependent apoptosis.

In this Christian Doppler laboratory we plan to study the molecular basis of cancer chemoprevention using mesalazine, aspirin, and curcumin as model compounds, to design and characterize novel molecules based on structure similarities, to test novel molecules in animal models, and to evaluate surrogate markers of early carcinogenesis in biopsy material for testing the effect of a novel mesalazine preparation (MMX-mesalazine) on CRC prevention in humans.

By identifying the mode of action of these key compounds, we expect to improve our molecular understanding of colon carcinogenesis and our ability to interfere with such. The designed novel compounds may have better efficacy and less toxicity, and thus improve cancer prevention, specifically in high-risk populations such as patients with inflammatory bowel disease or inherited cancer syndromes.

2. Chronic Inflammation and Colorectal Cancer:

Cancer is a disease that develops slowly. For most solid human tumors there is a 20 year interval between the carcinogen exposure and clinical detection of cancer. In ulcerative colitis, an idiopathic chronic inflammatory diseaseof the large intestine, colorectal cancer (CRC) development occurs at a higher rate and speed.The basic premise for the development of colorectal cancer is that cells accumulate millions of DNA mutations. The normal mutation rate, however, is insufficient to account for the multiple mutations observed in cancer cells. Therefore, changes that increase mutation rates are essential for tumor development. This so called "mutator phenotype" has been hypothesized for many years. It was first identified in tumors from patients with Lynch-syndrome (i.e. HNPCC or hereditary nonpolyposis colorectal cancer syndrome) in which multiple mutations within repetitive DNA-sequences (so called microsatellites) had been found. These multiple mutations in microsatellites are called microsatellite instability or MSI. In HNPCC, MSI is caused by germline mutations in DNA repair genes, the so called mismatch repair system (MMR). Indeed, MSI is regarded as fingerprint of inactivation of this DNA repair system that ensures DNA fidelity after each cell division. In ulcerative colitis, MSI is found in a minor form already in chronically inflamed mucosa suggesting that impairment of DNA fidelity during cell division is a key mechanism in the development of colitis-associated CRC. The reason for this is still unknown. Inhere we hypothesize that chronic inflammation in the colon creates an environment, which meets the criteria of a "mutator phenotype".

We intend to simulate such an environment in cell culture and we will test its effect on the DNA mutation rate in a recently developed system. Thereby, we transfer the clinical situation into the laboratory and may proof the existence of an inflammation-associated "mutator phenotype". The model will be useful for studying molecular mechanisms in the development of cancer. In particular, we also intend to study the effects of certain drugs and natural compounds for its ability to improve DNA fidelity during cell division. The results of our tests can be transferred into the clinical situations and may be used for prevention of CRC in ulcerative colitis and eventually also for other inflammation-associated cancers within the digestive tract.

3) Iron and Megakaryopoiesis:

Inflammatory bowel diseases (IBD) are associated with high platelet counts (thrombocytosis), platelet activation and an increased risk in thromboembolism, which is believed to be also caused by hypercoagulopathy. Thromboembolism and thrombocytosis is not an IBD specific but more a general event that was considered to be due to elevated levels of proinflammatory cytokines such as IL-1, TNF, or IL-6, which may stimulate (directly or indirectly) megakaryopoiesis and/or increase platelet activity. In this regard, a correlation of IL-6 (or IL-11) and platelet counts in Crohn's disease has been demonstrated.  However, other intestinal diseases with chronic iron deficiency anemia without such a systemic inflammatory reactions may also experience thrombocytosis (e.g. celiac disease).  Since iron deficiency anemia is associated with elevated EPO levels, it was thought that EPO induced stimulation of megakaryopoiesis may be responsible for the increase in platelets counts during iron deficiency anemia.  This proposal deals with an inflammation- and EPO-independent hypothesis of thrombocytosis in IBD.

4) Variant IL-10R1 Signaling:

Interleukin-10 (IL-10) is a regulatory protein that is secreted from immune cells during active inflammation. It is thought to counteract inappropriate inflammation by inducing a series of anti-inflammatory effects in the body. Animal models with IL-10 deficiency exhibit chronic inflammation of the bowel similar to human Crohn's disease, indicating that IL-10 regulates the immune response in the gut. All IL-10 induced signals are conducted over interaction of IL-10 with IL-10 receptor 1 (IL-10R1). We previously identified genetic variants of the IL-10R1, so called single nucleotide polymorphisms (SNP), SNP3 and SNP4. The worldwide distribution of these variants had been studied in 51 native populations. Both were most common in Semites and Caucasians (up to half of the population) and absent in Asians or Native Americans. These receptor variants changed the cellular response to IL-10. We also found that these variants protect individuals from development of some diseases but confer susceptibility to others supporting the notion that these genetic variations in the IL-10R1 are biologically relevant.

Inhere we propose to study the molecular mechanisms behind our observations. By using standard biochemical methods, we investigate the differential interaction of IL-10 and the IL-10R1 variants SNP3 and SNP4. Our research will help to better understand the impact of genetic variations on the cause of chronic inflammatory disease.