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Metabolomic characterization of human prostate cancer bone metastases reveals increased levels of cholesterol
Umeå University, Faculty of Science and Technology, Department of Chemistry.
Umeå University, Faculty of Science and Technology, Department of Chemistry.
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
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2010 (English)In: PLoS One, ISSN eISSN-1932-6203, Vol. 5, no 12, e14175- p.Article in journal (Refereed) Published
Abstract [en]

Background: Metastasis to the bone is one clinically important features of prostate cancer (PCa). Current diagnostic methods cannot predict metastatic PCa at a curable stage of the disease. Identification of metabolic pathways involved in the growth of bone metastases therefore has the potential to improve PCa prognostication as well as therapy.Methodology/Principal Findings: Metabolomics was applied for the study of PCa bone metastases (n = 20) in comparison with corresponding normal bone (n = 14), and furthermore of malignant (n = 13) and benign (n = 17) prostate tissue and corresponding plasma samples obtained from patients with (n = 15) and without (n = 13) diagnosed metastases and from men with benign prostate disease (n = 30). This was done using gas chromatography-mass spectrometry for sample characterization, and chemometric bioinformatics for data analysis. Results were verified in a separate test set including metastatic and normal bone tissue from patients with other cancers (n = 7). Significant differences were found between PCa bone metastases, bone metastases of other cancers, and normal bone. Furthermore, we identified metabolites in primary tumor tissue and in plasma which were significantly associated with metastatic disease. Among the metabolites in PCa bone metastases especially cholesterol was noted. In a test set the mean cholesterol level in PCa bone metastases was 127.30 mg/g as compared to 81.06 and 35.85 mg/g in bone metastases of different origin and normal bone, respectively (P = 0.0002 and 0.001). Immunohistochemical staining of PCa bone metastases showed intense staining of the low density lipoprotein receptor and variable levels of the scavenger receptor class B type 1 and 3-hydroxy-3-methylglutaryl-coenzyme reductase in tumor epithelial cells, indicating possibilities for influx and de novo synthesis of cholesterol.Conclusions/Significance: We have identified metabolites associated with PCa metastasis and specifically identified high levels of cholesterol in PCa bone metastases. Based on our findings and the previous literature, this makes cholesterol a possible therapeutic target for advanced PCa.

Abstract [sv]

Dottertumörer vid prostatacancer kan spåras via kolesterolDottertumörer i skelettet hos patienter med prostatacancer innehåller höga nivåer av kolesterol och olika aminosyror. Att mäta nivåerna är därför en möjlig väg för att spåra misstänkta dottertumörer. Det visar forskare vid Umeå universitet i en ny studie.Ofta är det förekomsten av dottertumörer, metastaser, som avgör allvaret vid en cancersjukdom. För att behandla patienter med avancerad prostatacancer är det därför viktigt att hitta och identifiera metastaser på ett tidigt stadium. Metastaser från prostatacancer finns ofta i skelettets ben.I studien har forskarna analyserat normal prostatavävnad och vävnad från benmetastaser från patienter med prostatacancer och andra cancersjukdomar. Forskarna har på detta sätt försökt hitta entydiga mönster som utmärker benmetastaser hos patienter med prostatacancer.Något oväntat fann forskarna höga halter av kolesterol i metastasvävnad från patienter med prostatacancer, jämfört med de andra undersökta vävnaderna.– Tumörcellerna verkar både kunna bilda kolesterol och ta upp kolesterol från omgivningen, till exempel från blodet. Vi tror att kolesterol används till olika processer som är viktiga för en tumörcell, till exempel för att den ska kunna växa och invadera omkringliggande vävnad, förklarar Pernilla Wikström, forskare vid institutionen för medicinsk biovetenskap.Spridd prostatacancer brukar behandlas genom att man blockerar produktionen eller effekten av det manliga könshormonet testosteron, så kallad kastrationsbehandling.– Kolesterol används möjligen också till att göra könshormon och det motverkar i sådana fall kastrationsbehandling. Vi håller nu på att utreda detta vidare, tillägger hon.Forskarna fann även höga nivåer av andra metaboliter, substanser som förekommer vid ämnesomsättning i kroppens celler och vävnader. Bland annat upptäckte de vissa aminosyror, och intressant nog gick några av dessa även att spåra i blod hos patienter med metastaser.För att analysera metaboliterna har forskarna använt sig av Sverigeledande teknik på SLU:s laboratorium för metabolomik vid kemiskt biologiskt centrum (KBC) som förestås av professor Thomas Moritz. Genom att haltbestämma metaboliter i olika vävnader eller kroppsvätskor hoppas forskarna kunna hitta specifika mönster av metaboliter för flera olika sjukdomar. Dessa metaboliter skulle sedan kunna mätas i blod hos patienter som till exempel har misstänkta metastaser.– Min forskargrupp har länge arbetat med att utveckla metoder för att använda metabolomik inom medicinska frågeställningar. Målet är att öka möjligheterna att diagnostisera, förstå och i förlängningen behandla allvarliga sjukdomar, säger Henrik Antti, forskare vid kemiska institutionen och handledare till doktoranden Elin Thysell, som genomfört analyserna.Pernilla Wikström och Henrik Antti, som ansvarat för studien, är överens om att de lyckats väl tack vare ett bra samarbete mellan forskare vid prekliniska och kliniska institutioner. Studien har involverat forskare vid kemiska institutionen och Computational Life Science Cluster (CliC), institutionen för medicinisk biovetenskap, Umeå Plant Science Centre (UPSC), samt kliniska forskare inom patologi, onkologi, ortopedi och urologi vid Umeå universitet. Det faktum att man i Umeå har tillgång till en av få biobanker i världen innehållande benmetastaser från patienter var också avgörande för studiens genomförande.

Place, publisher, year, edition, pages
2010. Vol. 5, no 12, e14175- p.
Identifiers
URN: urn:nbn:se:umu:diva-38404DOI: 10.1371/journal.pone.0014175ISI: 000284939600001OAI: oai:DiVA.org:umu-38404DiVA: diva2:376820
Available from: 2010-12-13 Created: 2010-12-13 Last updated: 2012-01-04Bibliographically approved
In thesis
1. Multivariate profiling of metabolites in human disease: Method evaluation and application to prostate cancer
Open this publication in new window or tab >>Multivariate profiling of metabolites in human disease: Method evaluation and application to prostate cancer
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

There is an ever increasing need of new technologies for identification of molecular markers for early diagnosis of fatal diseases to allow efficient treatment. In addition, there is great value in finding patterns of metabolites, proteins or genes altered in relation to specific disease conditions to gain a deeper understanding of the underlying mechanisms of disease development. If successful, scientific achievements in this field could apart from early diagnosis lead to development of new drugs, treatments or preventions for many serious diseases.  Metabolites are low molecular weight compounds involved in the chemical reactions taking place in the cells of living organisms to uphold life, i.e. metabolism. The research field of metabolomics investigates the relationship between metabolite alterations and biochemical mechanisms, e.g. disease processes. To understand these associations hundreds of metabolites present in a sample are quantified using sensitive bioanalytical techniques. In this way a unique chemical fingerprint is obtained for each sample, providing an instant picture of the current state of the studied system. This fingerprint or picture can then be utilized for the discovery of biomarkers or biomarker patterns of biological and clinical relevance.

In this thesis the focus is set on evaluation and application of strategies for studying metabolic alterations in human tissues associated with disease. A chemometric methodology for processing and modeling of gas chromatography-mass spectrometry (GC-MS) based metabolomics data, is designed for developing predictive systems for generation of representative data, validation and result verification, diagnosis and screening of large sample sets.

The developed strategies were specifically applied for identification of metabolite markers and metabolic pathways associated with prostate cancer disease progression. The long-term goal was to detect new sensitive diagnostic/prognostic markers, which ultimately could be used to differentiate between indolent and aggressive tumors at diagnosis and thus aid in the development of personalized treatments. Our main finding so far is the detection of high levels of cholesterol in prostate cancer bone metastases. This in combination with previously presented results suggests cholesterol as a potentially interesting therapeutic target for advanced prostate cancer. Furthermore we detected metabolic alterations in plasma associated with metastasis development. These results were further explored in prospective samples attempting to verify some of the identified metabolites as potential prognostic markers.

Place, publisher, year, edition, pages
Umeå: Umeå Universitet, 2012. 43 p.
Keyword
metabolite profiling, metabolomics, predictive metabolomics, mass spectrometry, GC-MS, biomarkers, chemometrics, design of experiments, multivariate data analysis, prostate cancer, bone metastases, plasma
National Category
Other Medical Sciences not elsewhere specified
Research subject
biological chemistry
Identifiers
urn:nbn:se:umu:diva-50968 (URN)978-91-7459-344-0 (ISBN)
Public defence
2012-01-27, KBC-huset, KB3B1, Umeå universitet, Umeå, 10:00 (Swedish)
Opponent
Supervisors
Available from: 2012-01-04 Created: 2012-01-02 Last updated: 2012-01-11Bibliographically approved

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Thysell, ElinSurowiec, IzabellaHörnberg, EmmaCrnalic, SeadWidmark, AndersStattin, PärBergh, AndersAntti, HenrikWikström, Pernilla
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