title: Accumulation of small hyaluronan oligosaccharides in tumour interstitial fluid correlates with lymphatic invasion and lymph node metastasis.
abstract: BACKGROUND
  Association studies have implicated the glycosaminoglycan hyaluronan (hyaluronic acid, HA) and its degrading enzymes the hyaluronidases in tumour progression and metastasis. Oligosaccharides of degraded HA have been ascribed a number of biological functions that are not exerted by high-molecular-weight HA (HMW-HA). However, whether these small HA oligosaccharides (sHA) have a role in tumour progression currently remains uncertain due to an inability to analyse their concentration in tumours.
  
  
  METHODS
  We report a novel method to determine the concentration of sHA ranging from 6 to 25 disaccharides in tumour interstitial fluid (TIF). Levels of sHA were measured in TIF from experimental rat tumours and human colorectal tumours.
  
  
  RESULTS
  While the majority of HA in TIF is HMW-HA, concentrations of sHA up to 6 μg ml(-1) were detected in a subset of tumours, but not in interstitial fluid from healthy tissues. In a cohort of 72 colorectal cancer patients we found that increased sHA concentrations in TIF are associated with lymphatic vessel invasion by tumour cells and the formation of lymph node metastasis.
  
  
  CONCLUSIONS
  These data document for the first time the pathophysiological concentration of sHA in tumours, and provide evidence of a role for sHA in tumour progression.
authors.affiliation: 1] Medical Faculty Mannheim, University of Heidelberg, Ludolf-Krehl-Strasse 13-17, 68167 Mannheim, Germany [2] Karlsruhe Institute for Technology (KIT), Campus Nord, Institut für Toxikologie und Genetik, Postfach 3640, 76021 Karlsruhe, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Schmaus
authors.affiliation: 1] Medical Faculty Mannheim, University of Heidelberg, Ludolf-Krehl-Strasse 13-17, 68167 Mannheim, Germany [2] Karlsruhe Institute for Technology (KIT), Campus Nord, Institut für Toxikologie und Genetik, Postfach 3640, 76021 Karlsruhe, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Klusmeier
authors.affiliation: 1] Medical Faculty Mannheim, University of Heidelberg, Ludolf-Krehl-Strasse 13-17, 68167 Mannheim, Germany [2] Karlsruhe Institute for Technology (KIT), Campus Nord, Institut für Toxikologie und Genetik, Postfach 3640, 76021 Karlsruhe, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Rothley
authors.affiliation: Institut und Gemeinschaftspraxis für Pathologie an den St Vincentiuskliniken Karlsruhe, Südendstrasse 37, 76137 Karlsruhe, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Dimmler
authors.affiliation: Universitätsklinikum Tübingen, Department of Pathology, Liebermeisterstrasse 8, 72076 Tübingen, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Sipos
authors.affiliation: Institut und Gemeinschaftspraxis für Pathologie an den St Vincentiuskliniken Karlsruhe, Südendstrasse 37, 76137 Karlsruhe, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Faller
authors.affiliation: 1] Medical Faculty Mannheim, University of Heidelberg, Ludolf-Krehl-Strasse 13-17, 68167 Mannheim, Germany [2] Karlsruhe Institute for Technology (KIT), Campus Nord, Institut für Toxikologie und Genetik, Postfach 3640, 76021 Karlsruhe, Germany.
authors.forename: W
authors.initials: W
authors.lastname: Thiele
authors.affiliation: Medical Faculty Mannheim, University of Heidelberg, Ludolf-Krehl-Strasse 13-17, 68167 Mannheim, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Allgayer
authors.affiliation: Medical Faculty Mannheim, University of Heidelberg, Ludolf-Krehl-Strasse 13-17, 68167 Mannheim, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Hohenberger
authors.affiliation: Medical Faculty Mannheim, University of Heidelberg, Ludolf-Krehl-Strasse 13-17, 68167 Mannheim, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Post
authors.affiliation: 1] Medical Faculty Mannheim, University of Heidelberg, Ludolf-Krehl-Strasse 13-17, 68167 Mannheim, Germany [2] Karlsruhe Institute for Technology (KIT), Campus Nord, Institut für Toxikologie und Genetik, Postfach 3640, 76021 Karlsruhe, Germany.
authors.forename: J P
authors.initials: JP
authors.lastname: Sleeman
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism* / Q000556:secondary; D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism*; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000473:pathology; D045604:Extracellular Fluid / Q000378:metabolism*; D006801:Humans; D006820:Hyaluronic Acid / Q000378:metabolism*; D008207:Lymphatic Metastasis; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D051381:Rats
chemical_list: D014408:Biomarkers, Tumor; D006820:Hyaluronic Acid