title: Human prostate cancer in a clinically relevant xenograft mouse model: identification of β(1,6)-branched oligosaccharides as a marker of tumor progression.
abstract: OBJECTIVE
  To establish xenograft mouse models of metastatic and nonmetastatic human prostate cancer and to apply these models to the search for aberrant glycosylation patterns associated with tumor progression in vivo and in patients.
  
  
  METHODS
  Prostate cancer cells (LNCaP, PC-3, LuCaP 23.1, and DU-145) were xenografted subcutaneously into immunodeficient pfp(-/-)/rag2(-/-) mice. Tumor growth and metastasis formation were quantified and as altered glycosylation patterns have been associated with metastasis formation in several other malignancies, prostate cancer cells were profiled by a quantitative real-time PCR (qRT-PCR) glycosylation array and compared with normal human prostate cells. The activity of upregulated glycosyltransferases was analyzed by their sugar residues end products using lectin histochemistry on primary tumors and metastases in the animal experiments and on 2,085 clinical samples.
  
  
  RESULTS
  PC-3 cells produced the largest number of spontaneous lung metastases, followed by LNCaP and LuCaP 23.1, whereas DU-145 was nonmetastatic. qRT-PCR revealed an upregulation of β1,6-N-acetylglucosaminyltransferase-5b (Mgat5b) in all prostate cancer cell lines. Mgat5b products [β(1,6)-branched oligosaccharides] were predominantly detectable in metastatic xenografts as shown by increased binding of Phaseolus vulgaris leukoagglutinin (PHA-L). The percentage of prostate cancer patients who were PHA-L positive was 86.5. PHA-L intensity correlated with serum prostate-specific antigen and a cytoplasmic staining negatively affected disease-free survival.
  
  
  CONCLUSIONS
  We show a novel xenograft mouse model for human prostate cancer respecting the complete metastatic cascade. Specific glycosylation patterns reveal Mgat5b products as relevant markers of both metastatic competence in mice and disease-free survival in patients. This is the first description of Mgat5b in prostate cancer indicating a significant biologic importance of β(1,6)-branched oligosaccharides for prostate cancer progression.
authors.affiliation: Department of Anatomy and Experimental Morphology, University Cancer Center Hamburg, Hamburg, Germany. to.lange@uke.de
authors.forename: Tobias
authors.initials: T
authors.lastname: Lange
authors.forename: Sebastian
authors.initials: S
authors.lastname: Ullrich
authors.forename: Imke
authors.initials: I
authors.lastname: Müller
authors.forename: Michael F
authors.initials: MF
authors.lastname: Nentwich
authors.forename: Katrin
authors.initials: K
authors.lastname: Stübke
authors.forename: Susanne
authors.initials: S
authors.lastname: Feldhaus
authors.forename: Christine
authors.initials: C
authors.lastname: Knies
authors.forename: Olaf J C
authors.initials: OJ
authors.lastname: Hellwinkel
authors.forename: Robert L
authors.initials: RL
authors.lastname: Vessella
authors.forename: Claudia
authors.initials: C
authors.lastname: Abramjuk
authors.forename: Mario
authors.initials: M
authors.lastname: Anders
authors.forename: Jennifer
authors.initials: J
authors.lastname: Schröder-Schwarz
authors.forename: Thorsten
authors.initials: T
authors.lastname: Schlomm
authors.forename: Hartwig
authors.initials: H
authors.lastname: Huland
authors.forename: Guido
authors.initials: G
authors.lastname: Sauter
authors.forename: Udo
authors.initials: U
authors.lastname: Schumacher
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism*; D045744:Cell Line, Tumor; D002648:Child; D004195:Disease Models, Animal; D018450:Disease Progression; D006801:Humans; D037102:Lectins / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008875:Middle Aged; D017351:N-Acetylglucosaminyltransferases / Q000378:metabolism; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D009419:Nerve Tissue Proteins / Q000378:metabolism; D025942:Oligosaccharides, Branched-Chain / Q000378:metabolism*; D010835:Phytohemagglutinins / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding; D014183:Transplantation, Heterologous; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D037102:Lectins; D009419:Nerve Tissue Proteins; D025942:Oligosaccharides, Branched-Chain; D010835:Phytohemagglutinins; C100156:leukoagglutinins, plants; C479741:MGAT5B protein, human; D017351:N-Acetylglucosaminyltransferases