Summary
In vitro methods have shown that cancer invasion results from the balance of activation and inactivation of invasion-suppressor and invasion-promoter molecules. Such methods constitute micro-ecosystems that differ from one another mainly by their substrate for invasion, namely components of the basement membrane; collagen type 1 gels; monolayers of different cell types; fragments of different organs. The E-cadherin/catenin complex is an invasion-suppressor complex, the function of which was well documented in experimental and clinical cancer. Loss of E-cadherin resulted in the expression of the invasive phenotype. In a human colon cancer cell line, round cell variants that were E-cadherin-positive, α-catenin negative and invasive reproducibly emerged from epithelioid subclones that were E-cadherin-positive, α-cateninpositive and noninvasive. The E-cadherin/catenin complex was downregulated by synthetic decapeptides that are homologous or identical to the HAV region of the first extracellular domain of E-caderin. Downregulation of the complex at its intracellular side occurs through tyrosine phosphorylation of β-catenin. Upregulation of the function of the complex with inhibition of invasion was demonstrated in variants of the human MCF-7 breast cancer cell family using in vitro methods.
Zusammenfassung
Aktivierung und Inaktivierung von Invasions-Suppressor-Molekülen: eine in vitro-Analyse
In vitro-Methoden haben aufgezeigt, daß Krebsinvasivität das Ergebnis eines gestörten Gleichgewichts zwischen Aktivierung bzw. Inaktivierung von Invasions-Suppressor- sowie Invasions-Promotor-Molekülen ist. Diese in vitro-Methoden verwenden Mikro-Ökosysteme, die sich hauptsächlich im Invasions-Substrat unterscheiden, z.B. Teile der Basalmembran, Kollagen Typ I Gele, einlagige Zellkulturen und Fragmente aus verschiedenen Organen. Der E-Kadherin/Katenin Komplex ist ein Invasionshemmer, dessen Funktion für experimentelle und klinische Krebsformen gut dokumentiert ist. Verlust von E-Kadherin führt zu hochinvasiven Phaenotypen. In einer menschlichen Kolonkrebs-Zelllinie finden sich runde Zellvarianten, die E-Kadherin positiv und α-Katenin negativ und invasiv sind. Diese Zellen entwickelten sich aus epitheloiden Subklonen, die E-Kadherin positiv, α-Katenin positiv and nicht-invasiv waren. Der, E-Kadherin/Katenin Komplex wurde durch synthetische Dekapeptide vermindert, die homolog bzw. identisch zu der HAV Region der ersten extrazellulären Domäne von EKadherin waren. Eine Hemmung der Komplexbildung ist auch an der Membraninnenseite durch Typrosin-Phosphorylierung von ß-Katenin möglich. Eine Förderung des Komplexes mit Hemmung der Invasivität wurde an menschlichen MCF-7 Brustkrebszellen durch in vitroInvasionsstudien nachgewiesen.
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Mareel, M. et al. (1997). Activation and Inactivation of Invasion-Suppressor Molecules: In Vitro Analysis. In: Schöffl, H., et al. Forschung ohne Tierversuche 1996. Ersatz- und Ergänzungsmethoden zu Tierversuchen. Springer, Vienna. https://doi.org/10.1007/978-3-7091-6833-2_16
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