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CYP2W1 in Colorectal Cancer – Aspects of Risk, Prognosis and Future Treatment Options

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CYP2W1 in Colorectal Cancer – Aspects of Risk, Prognosis and Future Treatment Options Department of Molecular Medicine and Surgery, Division of Surgery Karolinska Institutet, Stockholm CYP2W1 in colorectal cancer – aspects of risk, prognosis and future treatment options Kristina Stenstedt Stockholm 2013 1 Kristina Stenstedt All previously published papers were reproduced with permission from the publisher. Published by Karolinska Institutet Printed by Universitetsservice AB Layout Ringvor Hägglöf ©Kristina Stenstedt 2013 ISBN: 978-91-7549-332-9 2 Live as if you were going to die tomorrow, Learn as if you were going to live forever. Mahatma Gandhi 3 Kristina Stenstedt 4 Contents ABSTRACT......................................................................................................... 7 LIST OF ABBREVIATIONS ............................................................................. 9 LIST OF PUBLICATIONS ............................................................................... 11 THESIS AT A GLANCE ................................................................................... 13 INTRODUCTION ............................................................................................ 15 Colorectal cancer – epidemiology ............................................................. 15 Staging and survival .................................................................................. 15 Treatment of colorectal cancer .................................................................. 16 Colorectal cancer risk – inherited factors ................................................. 17 High penetrance genes .................................................................. 18 Low penetrance genes.................................................................... 19 Colorectal cancer risk – environmental factors.......................................... 20 Physical activity ............................................................................ 20 Diet ................................................................................................ 21 Carcinogenic compounds in food .................................................. 22 Interactions between diet and low penetrance genes ..................... 23 Development of colorectal cancer – molecular mechanisms...................... 23 Genetics.......................................................................................... 23 Epigenetics ..................................................................................... 25 Colonic stem cells and cancer ........................................................ 26 Tumor stroma and inflammation .................................................... 29 Biology of the invasion – metastasis cascade ................................ 30 Prognostic and predictive factors ............................................................... 32 Cytochromes P450 – a family of enzymes ................................................. 35 Polymorphism in CYP genes ......................................................... 36 CYPs and cancer risk ..................................................................... 36 CYPs and prognosis........................................................................ 37 CYP2W1 .................................................................................................... 37 Regulation of the CYP2W1 transcription ...................................... 38 Polymorphism in the CYP2W1 gene .............................................. 38 Substrates to CYP2W1 ................................................................... 38 Using tumor specific CYP2W1 as a target for pro-drug activation. 39 AIMS OF THE THESIS ..................................................................................... 41 MATERIALS AND METHODS ........................................................................ 43 Patients ....................................................................................................... 43 Immunofluorescence .................................................................................. 45 Immunohistochemistry .............................................................................. 45 5 Kristina Stenstedt Polymerase chain reaction .............................................................................. 46 cDNA constructs, transfections and cell viability assay ................................. 47 CYP2W1 functional assay .............................................................................. 48 Statistical Methods........................................................................................... 48 RESULTS AND DISCUSSION .............................................................................. 49 CYP2W1 expression in primary colorectal tumors ........................................ 49 CYP2W1 expression in primary tumors and relation to prognosis................. 50 Polymorphism in the CYP2W1 gene and colorectal cancer risk..................... 53 CYP2W1 expression in colorectal metastsases............................................... 53 CONCLUSIONS ..................................................................................................... 57 FUTURE PERSPECTIVES .................................................................................... 59 POPULÄRVETENSKAPLIG SAMMANFATTNING PÅ SVENSKA.................. 61 ACKNOWLEDGEMENTS .................................................................................... 63 REFERENCES ........................................................................................................ 67 PAPERS l-lV 6 AbstrACt Colorectal cancer (CRC) is a common disease and a major cause of cancer related death globally. Prognosis is rather good in early stages but worse in cases with disseminated disease. There is a constant need of developing all treatment modalities, which also has been done over the last decades. There are needs to find predictive markers in order to assess who will and who will not benefit of chemotherapy, just as there are needs to develop drugs targeting novel pathways and proteins prevalent in primary tumors and metastases. CYP2W1 is a member of the cytochrome P450 superfamily of enzymes with unknown physiological functions but found to have the capacity to metabolize both carcinogens and various other xenobiotic substances. It is expressed in fetal rat colonic tissue and in human colorectal tumors, but not to our knowledge in any adult normal human tissue. CYP2W1 expression, both mRNA and protein, has previously been studied in a material consisting of about 50 colorectal tumor samples. We wanted to investigate the extent of CYP2W1 expression in a larger tumor material using immunohistochemistry. We found it also interesting to see if CYP2W1 expression affects prognosis. Another aim of the thesis was to assess the association between polymorphism in the CYP2W1 gene and risk to develop CRC. A last aim was to evaluate the CYP2W1 expression in metastases. For the first aim, we used three different patient cohorts, two of which were derived from a randomized Nordic trial aiming to compare no adjuvant versus adjuvant treatment in patients with stage II and III CRC. These cohorts consisted of 162 and 235 patients respectively. The third patient cohort consisted of 96 patients being resected for liver metastases from CRC. All tumor manifestations in these patients were investigated with immunohistochemistry, addressing both the first and the last aim, and the findings indicate that CYP2W1 is expressed at high levels in between 26-36% of the primary tumors. It is expressed in about one third of lymph node metastases and almost half of the liver metastases. We performed two investigations regarding CYP2W1 as a prognostic factor using the two cohorts from the Nordic study (n=162 and n=235). In the first study, high CYP2W1 expression was of independent prognostic value for poor survival together with stage. In the second study aiming to reproduce this, the result was not as clear-cut, CYP2W1 was of prognostic value only in multivariate analysis but not in univariate analysis. In the subgroup of patients with stage III CRC (n=132), CYP2W1 expression was of independent prognostic value. The third aim was addressed using a material of DNA from individuals in a large case- control study aiming to investigate various polymorphisms and their relation to CRC risk. DNA from 1785 CRC patients and 1761 control subject was analyzed regarding 7 Kristina Stenstedt three CYP2W1 variants. We also experimentally assessed enzymatic activity of the gene products of the variants studied. No difference was seen, neither in CRC risk between cases and controls, nor in enzymatic activity between the three variant proteins. In conclusion, CYP2W1 seems to be expressed in about one third of primary CRC and half of the liver metastases. The association with prognosis in CRC requires further studies to be elucidated. Genetic polymorphism in the CYP2W1 gene does not seem to have any impact on CRC risk. The tumor specific expression of a catalytic enzyme in CRC and metastases is interesting in the aspect of future targeted anti-cancer therapies. 8 List of AbbreviAtions AA Arachidonic acid AhR Aryl hydrocarbon receptor Ala Alanine APC Adenomatous polyposis coli ARNT Aryl hydrocarbon receptor nuclear translocator BMP Bone morphogenetic protein COX Cyclooxygenase CRC Colorectal cancer CRP C-reactive protein CYP Cytochrome P450 EGFR Epidermal growth factor receptor EMT Epithelial – mesenchymal transition FAP Familial adenomatous polyposis GWAS Genome-wide association studies HCA
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