Integrins as antimetastatic targets of RGD-independent snake venom components in liver metastasis [corrected]

TY - JOUR

T1 - Integrins as antimetastatic targets of RGD-independent snake venom components in liver metastasis [corrected]

AU - Rosenow, Felix

AU - Ossig, Rainer

AU - Thormeyer, Dorit

AU - Gasmann, Peter

AU - Schlüter, Kerstin

AU - Brunner, Georg

AU - Haier, Jörg

AU - Eble, Johannes A

PY - 2008/2

Y1 - 2008/2

N2 - Metastasis comprises several subsequent steps including local invasion and intravasation at the primary site, then their adhesion/arrest within the vessels of host organs followed by their extravasation and infiltration into the target organ stroma. In contrast to previous studies which have used aspartate-glycine-arginine (RGD) peptides and antibodies against integrins, we used rare collagen- and laminin-antagonizing integrin inhibitors from snake venoms to analyze the colonization of the liver by tumor cells both by intravital microscopy and in vitro. Adhesion of liver-targeting tumor cells to the sinusoid wall components, laminin-1 and fibronectin, is essential for liver metastasis. This step is inhibited by lebein-1, but not by lebein-2 or rhodocetin. Both lebeins from the Vipera lebetina venom block integrin interactions with laminins in an RGD-independent manner. Rhodocetin is an antagonist of alpha2beta1 integrin, a collagen receptor on many tumor cells. Subsequent to tumor cell arrest, extravasation into the liver stroma and micrometastasis are efficiently delayed by rhodocetin. This underlines the importance of alpha2beta1 integrin interaction with the reticular collagen I-rich fibers in liver stroma. Antagonists of laminin- and collagen-binding integrins could be valuable tools to individually block the direct interactions of tumor cells with distinct matrix components of the Disse space, thereby reducing liver metastasis.

AB - Metastasis comprises several subsequent steps including local invasion and intravasation at the primary site, then their adhesion/arrest within the vessels of host organs followed by their extravasation and infiltration into the target organ stroma. In contrast to previous studies which have used aspartate-glycine-arginine (RGD) peptides and antibodies against integrins, we used rare collagen- and laminin-antagonizing integrin inhibitors from snake venoms to analyze the colonization of the liver by tumor cells both by intravital microscopy and in vitro. Adhesion of liver-targeting tumor cells to the sinusoid wall components, laminin-1 and fibronectin, is essential for liver metastasis. This step is inhibited by lebein-1, but not by lebein-2 or rhodocetin. Both lebeins from the Vipera lebetina venom block integrin interactions with laminins in an RGD-independent manner. Rhodocetin is an antagonist of alpha2beta1 integrin, a collagen receptor on many tumor cells. Subsequent to tumor cell arrest, extravasation into the liver stroma and micrometastasis are efficiently delayed by rhodocetin. This underlines the importance of alpha2beta1 integrin interaction with the reticular collagen I-rich fibers in liver stroma. Antagonists of laminin- and collagen-binding integrins could be valuable tools to individually block the direct interactions of tumor cells with distinct matrix components of the Disse space, thereby reducing liver metastasis.

KW - Animals

KW - Antineoplastic Agents

KW - Carcinoma, Hepatocellular

KW - Cell Adhesion

KW - Cell Line, Tumor

KW - Cell Movement

KW - Collagen

KW - Colorectal Neoplasms

KW - Crotalid Venoms

KW - Fibronectins

KW - Humans

KW - Integrins

KW - Laminin

KW - Liver

KW - Liver Neoplasms

KW - Male

KW - Rats

KW - Rats, Sprague-Dawley

KW - Viper Venoms

M3 - SCORING: Journal article

C2 - 18283339

VL - 10

SP - 168

EP - 176

JO - NEOPLASIA

JF - NEOPLASIA

SN - 1476-5586

IS - 2

ER -