Integrins as antimetastatic targets of RGD-independent snake venom components in liver metastasis [corrected].
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.
Rosenow
Felix
F
Department of General Surgery, Muenster University Hospital, 48149 Muenster, Germany.
Ossig
Rainer
R
Thormeyer
Dorit
D
Gasmann
Peter
P
Schlüter
Kerstin
K
Brunner
Georg
G
Haier
Jörg
J
Eble
Johannes A
JA
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D003094:Collagen / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology; D003435:Crotalid Venoms / Q000494:pharmacology*; D005353:Fibronectins / Q000378:metabolism; D006801:Humans; D016023:Integrins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007797:Laminin / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D014757:Viper Venoms / Q000494:pharmacology*
D000970:Antineoplastic Agents; D003435:Crotalid Venoms; D005353:Fibronectins; D016023:Integrins; D007797:Laminin; D014757:Viper Venoms; C121346:laminin 1; C428664:lebein; C119730:rhodocetin; D003094:Collagen