title: Integrins can directly mediate metastatic tumor cell adhesion within the liver sinusoids.
abstract: Tumor cells can show different malignant properties regarding their ability for organ-specific metastasis formation. Their adhesive and invasive characteristics mediated by various cell adhesion molecules appear to be crucial for this process. Using intravital fluorescence microscopy, we analyzed the adhesive and invasive interactions of circulating human colon carcinoma cells within the microvasculature of the liver in rats. The involvement of different cell adhesion molecules in specific tumor cell-host organ interactions was investigated. Single-cell suspensions of human colon carcinoma with low (HT-29P) and high (HT-29LMM) metastatic potential were fluorescence labeled with calcein-AM and intra-arterially injected into Sprague-Dawley rats. Initial interactions between different cell lines and the microvasculature of the liver were observed over 30 minutes and semiquantitatively analyzed. Different integrin subunits, carbohydrate ligands, and vascular cell adhesion molecule-1 were inhibited using function-blocking antibodies or by enzymatic removal. Inhibition of sialyl-Lewis(a) (sLe(a)) or enzymatic removal of selectin carbohydrate ligands significantly reduced metastatic cell adhesion. In addition, alpha6-, beta1-, and beta4-integrins can directly mediate cell adhesion within the hepatic microcirculation. Furthermore, alpha2-, alpha6-, beta1-, and beta4-integrins are involved in early tumor cell extravasation into the liver parenchyma. Organ-specific formation of colorectal metastases appears to be mainly mediated by specific interactions between circulating carcinoma cells and the vessel wall of target organs but not mechanical entrapment. Selectin-sLe(a) interactions with sinusoidal endothelial cells can play a key role in organ-specific targeting, but direct integrin-mediated cell adhesion to extracellular matrix components in the space of Disse appears to be required for the successful formation of liver metastases.
authors.affiliation: Molecular Biology Laboratory, Department of General Surgery, University Hospital Münster, Münster, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Enns
authors.forename: Peter
authors.initials: P
authors.lastname: Gassmann
authors.forename: Kerstin
authors.initials: K
authors.lastname: Schlüter
authors.forename: Timo
authors.initials: T
authors.lastname: Korb
authors.forename: Hans-Ullrich
authors.initials: HU
authors.lastname: Spiegel
authors.forename: Norbert
authors.initials: N
authors.lastname: Senninger
authors.forename: Jörg
authors.initials: J
authors.lastname: Haier
mesh_terms: D000818:Animals; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000032:analysis; D003110:Colonic Neoplasms / Q000473:pathology*; D006801:Humans; D039641:Integrin beta Chains / Q000032:analysis / Q000502:physiology*; D008099:Liver / Q000473:pathology*; D008113:Liver Neoplasms / Q000556:secondary; D008297:Male; D008856:Microscopy, Fluorescence; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D015815:Cell Adhesion Molecules; D039641:Integrin beta Chains