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Metabolomic characterization of human prostate cancer bone metastases reveals increased levels of cholesterol
Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi. Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap.ORCID-id: 0000-0001-5875-4946
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2010 (Engelska)Ingår i: PLoS One, ISSN 1932-6203, Vol. 5, nr 12, artikel-id e14175Artikel i tidskrift (Refereegranskat) 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.

Ort, förlag, år, upplaga, sidor
Public Library of Science , 2010. Vol. 5, nr 12, artikel-id e14175
Nationell ämneskategori
Cancer och onkologi
Identifikatorer
URN: urn:nbn:se:umu:diva-38404DOI: 10.1371/journal.pone.0014175ISI: 000284939600001PubMedID: 21151972Scopus ID: 2-s2.0-78649944454OAI: oai:DiVA.org:umu-38404DiVA, id: diva2:376820
Tillgänglig från: 2010-12-13 Skapad: 2010-12-13 Senast uppdaterad: 2023-03-23Bibliografiskt granskad
Ingår i avhandling
1. Multivariate profiling of metabolites in human disease: Method evaluation and application to prostate cancer
Öppna denna publikation i ny flik eller fönster >>Multivariate profiling of metabolites in human disease: Method evaluation and application to prostate cancer
2012 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
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.

Ort, förlag, år, upplaga, sidor
Umeå: Umeå Universitet, 2012. s. 43
Nyckelord
metabolite profiling, metabolomics, predictive metabolomics, mass spectrometry, GC-MS, biomarkers, chemometrics, design of experiments, multivariate data analysis, prostate cancer, bone metastases, plasma
Nationell ämneskategori
Övrig annan medicin och hälsovetenskap
Forskningsämne
biologisk kemi
Identifikatorer
urn:nbn:se:umu:diva-50968 (URN)978-91-7459-344-0 (ISBN)
Disputation
2012-01-27, KBC-huset, KB3B1, Umeå universitet, Umeå, 10:00 (Svenska)
Opponent
Handledare
Tillgänglig från: 2012-01-04 Skapad: 2012-01-02 Senast uppdaterad: 2018-06-08Bibliografiskt granskad

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Thysell, ElinHörnberg, EmmaCrnalic, SeadWidmark, AndersStattin, PärBergh, AndersAntti, HenrikWikström, Pernilla

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Thysell, ElinHörnberg, EmmaCrnalic, SeadWidmark, AndersStattin, PärBergh, AndersAntti, HenrikWikström, Pernilla
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Kemiska institutionenPatologiInstitutionen för kirurgisk och perioperativ vetenskapOnkologiUrologi och andrologi
Cancer och onkologi

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