Focal adhesion kinase regulates metastatic adhesion of carcinoma cells within liver sinusoids

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 -