Multi-Level Molecular Characterisation of Prostate Cancer
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Prostate cancer is the most common malignancy in Norwegian men, and represents a substantial health burden. The disease is heterogeneous, ranging from slow growing and indolent, to very aggressive and lethal. One of the major unsolved clinical challenges is to accurately separate indolent from harmful disease at an early time point. This causes substantial overtreatment of patients with harmless cancers, as well as undertreatment of patients with aggressive cancers. To enable improved treatment selection, an increased understanding of the molecular characteristics of prostate cancer progression is needed. In this thesis, multi-level molecular analyses of gene expression and metabolism were performed in an integrated fashion on prostate tissue samples. The aim was to obtain more comprehensive knowledge of prostate cancer aggressiveness, and to identify candidate biomarkers for improved risk stratification of prostate cancer patients. Gene expression analysis is a method that detects active genes; it can indicate which molecular processes occur in cells and tissue. The expression of genes is the instruction for which proteins are produced in the cells. Proteins are components of cellular signalling pathways, where the pathway activity can be altered to favour cancer survival. Activation of the Wnt signalling pathway may increase the cells’ motility, and can therefore be exploited by cancer cells to gain invasive and metastatic properties. The work in this thesis showed increased activation of a subgroup of the Wnt pathway, called the non-canonical Wnt pathway. By using a set of genes representing the non-canonical Wnt pathway (NCWP), combined with markers of increased cell mobility (epithelial-mesenchymal transition (EMT)), a gene signature coined NCWP-EMT was developed. An increased signature score suggests increased activation of this pathway. High signature score, representing increased activation of the pathway, was associated with aggressive cancer, where more patients experienced recurrent and metastatic disease after surgery. The signature may therefore have clinical potential to improve the discrimination of aggressive from indolent prostate cancer at an early time point. One of the signature members, secreted frizzled-related protein 4 (SFRP4), was further investigated on its own. The expression level of SFRP4 was shown to be a predictor for aggressive, recurrent and metastatic disease, and this was validated in several independent patient cohorts, and in a total of 1884 patients. SFRP4 alone, may therefore have potential as a biomarker for prediction of prostate cancer outcome. Changes in the genome can alter gene expression, and an example of this is a fusion of two genes, called TMPRSS2-ERG. This gene fusion is found in approximately half of malignant prostate tumours, however, little is known about its relation to other molecular processes, such as cancer cell metabolism. In this thesis, a distinctive metabolic profile was seen in cancer tissue possessing TMPRSS2-ERG, and this profile was similar to metabolic alterations previously observed in aggressive prostate cancer. Metabolism in tissues and cells can be studied by magnetic resonance (MR) spectroscopy. Cancer cell metabolism differ from healthy cells, as cancer often prioritise growth which require increased energy production and synthesis of new building blocks. Reprogramming of metabolism is therefore regarded as one of the hallmarks of cancer cells. The normal prostate cells produce and excrete high levels of the metabolite citrate for the prostatic fluid. Previously, a reduced levels of citrate have been detected in prostate cancer compared with healthy tissue, and this is likely due to citrate being used for energy and fatty acid production, rather than production and excretion. Furthermore, alterations to polyamine metabolism, and in particular to spermine, are important in prostate cancer, where decreased spermine concentration has been associated with the disease. In this thesis, reduced concentrations of both citrate and spermine were detected in cancer tissue samples containing the TMPRSS2-ERG gene fusion, samples with a high score of the non-canonical Wnt pathway signature, and samples with a high expression level of SFRP4. This suggests that citrate and spermine have great potential as tissue biomarkers of prostate cancer. Importantly, these metabolic alterations were also detected by non-invasive patient MR examination, which is therefore a candidate as a prognostic tool in prostate cancer diagnosis. To summarise, the work presented in this thesis shows that the TMPRSS2-ERG gene fusion, the non-canonical Wnt pathway, and SFRP4 expression are all associated with reprogramming of prostate cancer metabolism. Additionally, activation of the non-canonical Wnt pathway and the expression level of SFRP4 were associated with recurrent and metastatic disease after surgery. Further investigation of these aggressive molecular characteristics may lead to clinical biomarkers for improved early risk stratification in prostate cancer patients.
Has partsPaper 1: Hansen, Ailin Falkmo; Sandsmark, Elise; Rye, Morten Beck; Wright, Alan J; Bertilsson, Helena; Richardsen, Elin; Viset, Trond; Bofin, Anna M.; Angelsen, Anders; Selnæs, Kirsten Margrete; Bathen, Tone Frost; Tessem, May-Britt. Presence of TMPRSS2-ERG is associated with alterations of the metabolic profile in human prostate cancer. OncoTarget 2016 https://doi.org/10.18632/oncotarget.9817 licensed under a Creative Commons Attribution 3.0 License.
Paper 2: Sandsmark, Elise; Hansen, Ailin Falkmo; Selnæs, Kirsten Margrete; Bertilsson, Helena; Bofin, Anna M.; Wright, Alan J.; Viset, Trond; Richardsen, Elin; Drabløs, Finn Sverre; Bathen, Tone Frost; Tessem, May-Britt; Rye, Morten Beck. A novel non-canonical Wnt signature for prostate cancer aggressiveness. OncoTarget 2016 ;Volum 8.(6) s. 9572-9586 https://doi.org/10.18632/oncotarget.14161
Paper 3: Sandsmark E, Andersen MK, Bofin AM, Bertilsson H, Drabløs F, Bathen TF, Rye MB, Tessem MB. SFRP4 gene expression is increased in aggressive prostate cancer - Is not included due to copyright