Focal adhesion kinase regulates metastatic adhesion of carcinoma cells within liver sinusoids
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Focal adhesion kinase regulates metastatic adhesion of carcinoma cells within liver sinusoids. / von Sengbusch, Anke; Gassmann, Peter; Fisch, Katja M; Enns, Andreas; Nicolson, Garth L; Haier, Jörg.
In: AM J PATHOL, Vol. 166, No. 2, 02.2005, p. 585-96.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Focal adhesion kinase regulates metastatic adhesion of carcinoma cells within liver sinusoids
AU - von Sengbusch, Anke
AU - Gassmann, Peter
AU - Fisch, Katja M
AU - Enns, Andreas
AU - Nicolson, Garth L
AU - Haier, Jörg
PY - 2005/2
Y1 - 2005/2
N2 - Organ-specific tumor cell adhesion to extracellular matrix (ECM) components and cell migration into host organs often involve integrin-mediated cellular processes that can be modified by environmental conditions acting on metastasizing tumor cells, such as shear forces within the blood circulation. Since the focal adhesion kinase (FAK) appears to be essential for the regulation of the integrin-mediated adhesive and migratory properties of tumor cells, its role in early steps of the metastatic cascade was investigated using in vitro and in vivo approaches. Human colon and hepatocellular carcinoma cells were used to study adhesive properties under static conditions and in a parallel plate laminar flow chamber in vitro. In addition, intravital fluorescence microscopy was used to investigate early interactions between circulating tumor cells and the microvasculature of potential target organs in vivo. Shear forces caused by hydrodynamic fluid flow induced Tyr-hyperphosphorylation of FAK in cell monolayers. Reduced expression of FAK or its endogenous inhibition by FAK-related non-kinase (FRNK) interfered with early adhesion events to extracellular matrix components under flow conditions. In contrast, tumor cell adhesion to endothelial cells under these conditions was not affected. Furthermore, down-regulation of FAK inhibited metastatic cell adhesion in vivo within the liver sinusoids. In summary, FAK appears to be involved in early events of integrin-mediated adhesion of circulating carcinoma cells under fluid flow in vitro and in vivo. This kinase may take part in the establishment of definitive adhesive interactions that enable adherent tumor cells to resist fluid shear forces, resulting in an organ-specific formation of distant metastases.
AB - Organ-specific tumor cell adhesion to extracellular matrix (ECM) components and cell migration into host organs often involve integrin-mediated cellular processes that can be modified by environmental conditions acting on metastasizing tumor cells, such as shear forces within the blood circulation. Since the focal adhesion kinase (FAK) appears to be essential for the regulation of the integrin-mediated adhesive and migratory properties of tumor cells, its role in early steps of the metastatic cascade was investigated using in vitro and in vivo approaches. Human colon and hepatocellular carcinoma cells were used to study adhesive properties under static conditions and in a parallel plate laminar flow chamber in vitro. In addition, intravital fluorescence microscopy was used to investigate early interactions between circulating tumor cells and the microvasculature of potential target organs in vivo. Shear forces caused by hydrodynamic fluid flow induced Tyr-hyperphosphorylation of FAK in cell monolayers. Reduced expression of FAK or its endogenous inhibition by FAK-related non-kinase (FRNK) interfered with early adhesion events to extracellular matrix components under flow conditions. In contrast, tumor cell adhesion to endothelial cells under these conditions was not affected. Furthermore, down-regulation of FAK inhibited metastatic cell adhesion in vivo within the liver sinusoids. In summary, FAK appears to be involved in early events of integrin-mediated adhesion of circulating carcinoma cells under fluid flow in vitro and in vivo. This kinase may take part in the establishment of definitive adhesive interactions that enable adherent tumor cells to resist fluid shear forces, resulting in an organ-specific formation of distant metastases.
KW - Animals
KW - Carcinoma
KW - Carcinoma, Hepatocellular
KW - Cell Adhesion
KW - Cell Line, Tumor
KW - Collagen
KW - Colon
KW - Cytoskeletal Proteins
KW - Dose-Response Relationship, Drug
KW - Endothelium, Vascular
KW - Focal Adhesion Kinase 1
KW - Focal Adhesion Protein-Tyrosine Kinases
KW - Humans
KW - Immunoprecipitation
KW - Liver
KW - Liver Neoplasms
KW - Male
KW - Microcirculation
KW - Microscopy, Fluorescence
KW - Neoplasm Metastasis
KW - Neoplasms
KW - Oligonucleotides
KW - Paxillin
KW - Phosphoproteins
KW - Phosphorylation
KW - Phosphotyrosine
KW - Protein-Tyrosine Kinases
KW - Rats
KW - Rats, Sprague-Dawley
KW - Time Factors
KW - Transfection
KW - Tyrosine
U2 - 10.1016/S0002-9440(10)62280-8
DO - 10.1016/S0002-9440(10)62280-8
M3 - SCORING: Journal article
C2 - 15681841
VL - 166
SP - 585
EP - 596
JO - AM J PATHOL
JF - AM J PATHOL
SN - 0002-9440
IS - 2
ER -