title: Tumour-site-dependent expression profile of angiogenic factors in tumour-associated stroma of primary colorectal cancer and metastases.
abstract: BACKGROUND
  Tumour-associated stroma has a critical role in tumour proliferation. Our aim was to determine a specific protein expression profile of stromal angiogenic cytokines and matrix metalloproteinases (MMPs) to identify potential biomarkers or new therapy targets.
  
  
  METHODS
  Frozen tissue of primary colorectal cancer (n=25), liver (n=25) and lung metastases (n=23) was laser-microdissected to obtain tumour epithelial cells and adjacent tumour-associated stroma. Protein expression of nine angiogenic cytokines and eight MMPs was analysed using a multiplex-based protein assay.
  
  
  RESULTS
  We found a differential expression of several MMPs and angiogenic cytokines in tumour cells compared with adjacent tumour stroma. Cluster analysis displayed a tumour-site-dependent stromal expression of MMPs and angiogenic cytokines. Univariate analysis identified stromal MMP-2 and MMP-3 in primary colorectal cancer, stromal MMP-1, -2, -3 and Angiopoietin-2 in lung metastases and stromal MMP-12 and VEGF in liver metastases as prognostic markers (P>0.05, respectively). Furthermore, stroma-derived Angiopoietin-2 proved to be an independent prognostic marker in colorectal lung metastases.
  
  
  CONCLUSIONS
  Expression of MMPs and angiogenic cytokines in tumour cells and adjacent tumour stroma is dependent on the tumour site. Stroma-derived MMPs and angiogenic cytokines may be useful prognostic biomarkers. These data can be helpful to identify new agents for a targeted therapy in patients with colorectal cancer.
authors.affiliation: Department of General, Visceral and Transplantation Surgery, National Center for Tumor Diseases and Hamamatsu Tissue Imaging and Analysis (TIGA) Center, Institute for Medical Biometry and Informatics, University of Heidelberg, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Kahlert
authors.affiliation: Department of General, Visceral and Thoracic Surgery, University of Dresden, Fetscherstrasse 74, 01307 Dresden, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Pecqueux
authors.affiliation: Department of Medical Oncology, National Center for Tumor Diseases and Hamamatsu Tissue Imaging and Analysis (TIGA) Center, Institute for Medical Biometry and Informatics, University of Heidelberg, Heidelberg, Germany.
authors.forename: N
authors.initials: N
authors.lastname: Halama
authors.affiliation: Department of Thoracic Surgery, Thoraxklinik am Universitätsklinikum Heidelberg, Amalienstrasse 5, 69126 Heidelberg, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Dienemann
authors.affiliation: Department of Thoracic Surgery, Thoraxklinik am Universitätsklinikum Heidelberg, Amalienstrasse 5, 69126 Heidelberg, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Muley
authors.affiliation: Department of Thoracic Surgery, Thoraxklinik am Universitätsklinikum Heidelberg, Amalienstrasse 5, 69126 Heidelberg, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Pfannschmidt
authors.affiliation: Institute of Pathology, University of Heidelberg, Im Neuenheimer Feld 220, 69120 Heidelberg, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Lasitschka
authors.affiliation: Department of General, Visceral and Transplantation Surgery, National Center for Tumor Diseases and Hamamatsu Tissue Imaging and Analysis (TIGA) Center, Institute for Medical Biometry and Informatics, University of Heidelberg, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Klupp
authors.affiliation: Department of General, Visceral and Transplantation Surgery, National Center for Tumor Diseases and Hamamatsu Tissue Imaging and Analysis (TIGA) Center, Institute for Medical Biometry and Informatics, University of Heidelberg, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Schmidt
authors.affiliation: Department of General, Visceral and Transplantation Surgery, National Center for Tumor Diseases and Hamamatsu Tissue Imaging and Analysis (TIGA) Center, Institute for Medical Biometry and Informatics, University of Heidelberg, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany.
authors.forename: N
authors.initials: N
authors.lastname: Rahbari
authors.affiliation: Department of General, Visceral and Thoracic Surgery, University of Dresden, Fetscherstrasse 74, 01307 Dresden, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Reissfelder
authors.affiliation: Division of Biostatistics, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Kunz
authors.affiliation: Division of Biostatistics, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Benner
authors.affiliation: Medizinische Hochschule Hannover, Institut für Immunologie, Carl-Neuberg-Straße 1, 30625 Hannover, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Falk
authors.affiliation: Department of General, Visceral and Thoracic Surgery, University of Dresden, Fetscherstrasse 74, 01307 Dresden, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Weitz
authors.affiliation: Department of General, Visceral and Thoracic Surgery, University of Dresden, Fetscherstrasse 74, 01307 Dresden, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Koch
mesh_terms: D000368:Aged; D043925:Angiogenesis Inducing Agents / Q000378:metabolism*; D042702:Angiopoietin-2 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000556:secondary; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000556:secondary; D008297:Male; D020782:Matrix Metalloproteinases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D011379:Prognosis; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology*; D059467:Transcriptome; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism
chemical_list: D043925:Angiogenesis Inducing Agents; D042702:Angiopoietin-2; D014408:Biomarkers, Tumor; D016207:Cytokines; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D020782:Matrix Metalloproteinases