| dc.description.abstract | Prostate cancer is the most common form of malignancy inflicting men in the west and manifests
itself as a heterogeneous disease with a range of different clinical outcomes. Whereas some prostate
tumors grow slowly and may never become clinically significant, other tumors are aggressive and
require early and radical treatment. The different radical treatment options for prostate cancer have
several substantial side-effects, and it is therefore of interest to both the patients and the healthcare
system to avoid unnecessary treatment. Hence, it is important to identify which tumors are
aggressive and should be treated. Molecular characterization of tumors is important for finding and
developing novel diagnostic and prognostic biomarkers that can accurately identify which patients
would benefit from radical treatment.
The overall goal of this thesis was to gain increased biological knowledge of prostate cancer tissue
through a multi-omics approach. The aim was to identify metabolic and transcriptomic biomarkers
that are descriptive of prostate cancer development and can predict tumor aggressiveness and
clinical outcome. Transcriptomics is the study of the complete set of RNA transcripts, or gene
expression, made from DNA in a biological sample, e.g. a tissue sample, whereas metabolomics
investigates the chemical processes involving metabolites. The methods used in this work included;
gene expression analysis through DNA microarrays, histopathology, immunohistochemistry and
metabolic profiling through high resolution magic angle spinning magnetic resonance spectroscopy
(HR-MAS MRS) and matrix assisted laser desorption/ionization time-of-flight mass spectrometry
imaging (MALDI-TOF MSI).
The first paper investigated the gene expression of secreted frizzled-related protein 4 (SFRP4) across
nine independent patient cohorts. SFRP4 was shown to be significantly associated with prostate
cancer and aggressiveness, and was significantly inversely correlated with the metabolites citrate
and spermine, two metabolites whose reduced levels previously are identified as prognostic markers
for prostate cancer. Further, SFRP4 gene expression was a predictor of recurrence and metastatic
disease, making SFRP4 a potential biomarker for prostate cancer stratification.
Reactive stroma is a tissue feature commonly present in prostate tumors and is reported to predict a
worse clinical outcome. In the second paper, metabolic and transcriptomic profiling were performed
on prostate cancer tissue samples with low and high reactive stroma content. Genes and
metabolites related to immune processes were particularly significant and enriched in samples with
high reactive stroma content compared to low reactive stroma. The expression of genes related to
remodeling of the extracellular matrix (ECM) were also increased. Finally, in concordance with previous publications, high reactive stroma content was a significant predictor of recurrence even
when accounting for Grade Group, which is the standard histopathology grading system for prostate
cancer aggressiveness. This finding supports integrating reactive stroma assessment with the Grade
Group system in the clinic, although standardization of this assessment is needed.
MALDI-TOF MSI is an emerging method which allows measurement of the spatial distribution of
biological molecules, including metabolites and lipids. This is of special value for analyzing malignant
tissues such as prostate cancer which commonly have a heterogeneous tissue composition. In the
third paper, we tested the applicability of MALDI-TOF MSI for metabolic profiling of prostate cancer
tissue sections, using both ion modes. By pairwise comparing benign epithelium, stroma and cancer
tissue regions, we identified alterations in key metabolic processes. Notably, reduction of citrate and
spermine in cancer tissue compared to benign epithelium were validated, higher levels of the
antioxidant taurine were found in stroma compared to both benign and cancer epithelium and
higher levels of phospholipids indicated altered lipid metabolism. Interestingly, we identified
elevated levels of carnitine and acetylcarnitine, key metabolites of the carnitine shuttle which
facilitates oxidation of fatty acids, in cancer tissue compared to both stroma and benign epithelium.
This is a novel finding in prostate cancer tissue and further investigation of these metabolites as
biomarkers is warranted. Together with generally increased levels of phospholipids in cancer tissue,
this finding supports lipid metabolism as a key player in prostate cancer development.
In conclusion, by using a range of different metabolomics, transcriptomics and histology methods for
analyzing prostate cancer tissue samples, several molecular alterations were identified in this thesis.
SFRP4 gene expression is a potential biomarker for prostate cancer stratification, although further
assessment of its applicability as a biomarker is needed. Molecular characterization of reactive
stroma showed an increase of immune processes and ECM remodeling, and added extra support for
using reactive stroma assessment in clinical histopathology. Through MALDI-TOF MSI analyses of
prostate tissue, several biological molecules were detected as altered between different tissue
types, such as metabolites involved in lipid synthesis, �����-oxidation, prostatic secretory function and
inflammation. The differences in metabolite distributions between the defined tissue types,
showcase MALDI-TOF MSI as valuable metabolomics tool for analyzing heterogeneous tissue
samples and for biomarker discovery. | nb_NO |
