title: Angiogenesis in synchronous and metachronous colorectal liver metastases: the liver as a permissive soil.
abstract: OBJECTIVE
  Resection of a primary colorectal carcinoma (CRC) can be accompanied by rapid outgrowth of liver metastases, suggesting a role for angiogenesis. The aim of this study is to investigate whether the presence of a primary CRC is associated with changes in angiogenic status and proliferation/apoptotic rate in synchronous liver metastases and/or adjacent liver parenchyma.
  
  
  METHODS
  Gene expression and localization of CD31, HIF-1α, members of the vascular endothelial growth factor (VEGF) and Angiopoietin (Ang) system were studied using qRT-PCR and immunohistochemistry in colorectal liver metastases and nontumorous-adjacent liver parenchyma. Proliferation and apoptotic rate were quantified. Three groups of patients were included: (1) simultaneous resection of synchronous liver metastases and primary tumor (SS-group), (2) resection of synchronous liver metastases 3 to 12 months after resection of the primary tumor [late synchronous (LS-group)], and (3) resection of metachronous metastases >14 months after resection of the primary tumor (M-group).
  
  
  RESULTS
  In all 3 groups a higher expression of the angiogenic factors was encountered in adjacent liver parenchyma as compared to the metastases. VEGFR-2 gene expression was abundant in adjacent liver parenchyma in all 3 groups. VEGF-A and VEGFR-1 were prominent in adjacent parenchyma in the SS-group. The SS-group showed the highest Ang-2/Ang-1 ratio both in the metastases and the adjacent liver. This was accompanied by a high turnover of tumor cells.
  
  
  CONCLUSIONS
  In the presence of the primary tumor, the liver parenchyma adjacent to the synchronous liver metastases provides an angiogenic prosperous environment for metastatic tumor growth.
authors.affiliation: Department of Pathology and Medical Biology, Medical Biology Section, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Gesiena E
authors.initials: GE
authors.lastname: van der Wal
authors.forename: Annette S H
authors.initials: AS
authors.lastname: Gouw
authors.forename: Jan A A M
authors.initials: JA
authors.lastname: Kamps
authors.forename: Henk E
authors.initials: HE
authors.lastname: Moorlag
authors.forename: Marian L C
authors.initials: ML
authors.lastname: Bulthuis
authors.forename: Grietje
authors.initials: G
authors.lastname: Molema
authors.forename: Koert P
authors.initials: KP
authors.lastname: de Jong
mesh_terms: D000328:Adult; D000368:Aged; D017209:Apoptosis / Q000235:genetics; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000098:blood supply* / Q000473:pathology / Q000601:surgery; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics; D008099:Liver / Q000098:blood supply / Q000473:pathology; D008113:Liver Neoplasms / Q000098:blood supply* / Q000556:secondary* / Q000601:surgery; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D009378:Neoplasms, Multiple Primary / Q000098:blood supply* / Q000235:genetics / Q000473:pathology / Q000556:secondary* / Q000601:surgery; D016609:Neoplasms, Second Primary / Q000098:blood supply* / Q000235:genetics / Q000473:pathology / Q000556:secondary* / Q000601:surgery; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000473:pathology*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000235:genetics; D011379:Prognosis; D060888:Real-Time Polymerase Chain Reaction; D012259:Ribonuclease, Pancreatic / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008565:Membrane Proteins; C098069:PIGF protein, human; D019408:Platelet Endothelial Cell Adhesion Molecule-1; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2; C046366:angiogenin; D012259:Ribonuclease, Pancreatic