title: Metabolomic characterization of human prostate cancer bone metastases reveals increased levels of cholesterol.
abstract: 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.
  
  
  RESULTS
  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
  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.
authors.affiliation: Department of Chemistry, Umeå University, Umeå, Sweden.
authors.forename: Elin
authors.initials: E
authors.lastname: Thysell
authors.forename: Izabella
authors.initials: I
authors.lastname: Surowiec
authors.forename: Emma
authors.initials: E
authors.lastname: Hörnberg
authors.forename: Sead
authors.initials: S
authors.lastname: Crnalic
authors.forename: Anders
authors.initials: A
authors.lastname: Widmark
authors.forename: Annika I
authors.initials: AI
authors.lastname: Johansson
authors.forename: Pär
authors.initials: P
authors.lastname: Stattin
authors.forename: Anders
authors.initials: A
authors.lastname: Bergh
authors.forename: Thomas
authors.initials: T
authors.lastname: Moritz
authors.forename: Henrik
authors.initials: H
authors.lastname: Antti
authors.forename: Pernilla
authors.initials: P
authors.lastname: Wikström
mesh_terms: D001706:Biopsy; D001859:Bone Neoplasms / Q000473:pathology*; D001842:Bone and Bones / Q000473:pathology; D002784:Cholesterol / Q000737:chemistry / Q000378:metabolism*; D019295:Computational Biology / Q000379:methods; D008401:Gas Chromatography-Mass Spectrometry / Q000379:methods; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D008297:Male; D055432:Metabolomics / Q000379:methods*; D009362:Neoplasm Metastasis; D011471:Prostatic Neoplasms / Q000473:pathology; D012521:Sarcosine / Q000378:metabolism; D014018:Tissue Distribution
chemical_list: D002784:Cholesterol; D012521:Sarcosine