title: Tissue inhibitor of matrix metalloproteinase-1 expression in colorectal cancer liver metastases is associated with vascular structures.
abstract: Metastatic growth by colorectal cancer cells in the liver requires the ability of the cancer cells to interact with the new microenvironment. This interaction results in three histological growth patterns of liver metastases: desmoplastic, pushing, and replacement. In primary colorectal cancer several proteases, involved in the degradation of extracellular matrix components, are up-regulated. In liver metastases, their expression is growth pattern dependent. Tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) is a strong prognostic marker in plasma from colorectal cancer patients, with significant higher levels in patients with metastatic disease. We therefore wanted to determine the expression pattern of TIMP-1 in primary colorectal cancers and their matching liver metastases. TIMP-1 mRNA was primarily seen in α-smooth-muscle actin (α-SMA)-positive cells. In all primary tumors and liver metastases with desmoplastic growth pattern, TIMP-1 mRNA was primarily found in α-SMA-positive myofibroblasts located at the invasive front. Some α-SMA-positive cells with TIMP-1 mRNA were located adjacent to CD34-positive endothelial cells, identifying them as pericytes. This indicates that TIMP-1 in primary tumors and liver metastases with desmoplastic growth pattern has dual functions; being an MMP-inhibitor at the cancer periphery and involved in tumor-induced angiogenesis in the pericytes. In the liver metastases with pushing or replacement growth patterns, TIMP-1 was primarily expressed by activated hepatic stellate cells at the metastasis/liver parenchyma interface. These cells were located adjacent to CD34-positive endothelial cells, suggesting a function in tumor-induced angiogenesis. We therefore conclude that TIMP-1 expression is growth pattern dependent in colorectal cancer liver metastases.
authors.affiliation: The Finsen Laboratory, Rigshospitalet, Copenhagen, Denmark.|Biotech Research and Innovation Center (BRIC), University of Copenhagen, Copenhagen, Denmark.
authors.forename: Martin
authors.initials: M
authors.lastname: Illemann
authors.affiliation: The Finsen Laboratory, Rigshospitalet, Copenhagen, Denmark.|Biotech Research and Innovation Center (BRIC), University of Copenhagen, Copenhagen, Denmark.|Department of Oncology, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Rikke Helene Løvendahl
authors.initials: RH
authors.lastname: Eefsen
authors.affiliation: Academic Surgical Unit, University of Sheffield, Sheffield, England.
authors.forename: Nigel Charles
authors.initials: NC
authors.lastname: Bird
authors.affiliation: Academic Surgical Unit, University of Sheffield, Sheffield, England.
authors.forename: Ali
authors.initials: A
authors.lastname: Majeed
authors.affiliation: Department of Oncology, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Kell
authors.initials: K
authors.lastname: Osterlind
authors.affiliation: The Finsen Laboratory, Rigshospitalet, Copenhagen, Denmark.|Biotech Research and Innovation Center (BRIC), University of Copenhagen, Copenhagen, Denmark.
authors.forename: Ole Didrik
authors.initials: OD
authors.lastname: Laerum
authors.affiliation: The Finsen Laboratory, Rigshospitalet, Copenhagen, Denmark.|Biotech Research and Innovation Center (BRIC), University of Copenhagen, Copenhagen, Denmark.|Center for Research on Microscopic Structures, University of Costa Rica, San José, Costa Rica.
authors.forename: Warner
authors.initials: W
authors.lastname: Alpízar-Alpízar
authors.affiliation: The Finsen Laboratory, Rigshospitalet, Copenhagen, Denmark.|Biotech Research and Innovation Center (BRIC), University of Copenhagen, Copenhagen, Denmark.
authors.forename: Ida Katrine
authors.initials: IK
authors.lastname: Lund
authors.affiliation: The Finsen Laboratory, Rigshospitalet, Copenhagen, Denmark.|Biotech Research and Innovation Center (BRIC), University of Copenhagen, Copenhagen, Denmark.
authors.forename: Gunilla
authors.initials: G
authors.lastname: Høyer-Hansen
mesh_terms: D000199:Actins / Q000378:metabolism; D000328:Adult; D000368:Aged; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000098:blood supply* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008113:Liver Neoplasms / Q000098:blood supply / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000556:secondary*; D008297:Male; D008875:Middle Aged; D020286:Pericytes / Q000378:metabolism; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics* / Q000378:metabolism*
chemical_list: C541116:ACTA2 protein, human; D000199:Actins; C560822:TIMP1 protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1
keywords: TIMP-1; angiogenesis; desmoplasia; hepatic metastasis; histology