Gastrointestinal Tumors: Metastasis and Tetraspanins

Zusammenfassung

Tumoren des Magen-Darm-Traktes unter Einschluss von Malignomen des Magens, des Kolorektum, der Leber und des Pankreas umfassen weltweit über 50 % aller Tumoren. Die 5-Jahres-Überlebensrate schwankt zwischen über 50 % bei kolorektalen Tumoren und liegt unter 1 % beim Pankreaskarzinom, wobei Überlebenszeit und Sterblichkeitsrate bei Tumoren des Magen-Darm-Traktes in direkter Korrelation mit der Metastasierungskapazität stehen. Tetraspanine sind eine relativ neue Familie von Membranproteinen, die vornehmlich über die Bildung von Komplexen mit weiteren Tetraspaninen und einer Vielzahl weiterer Molekülfamilien agieren und diese in definierten Membrandomänen zusammenführen. Diese lipidreichen Membrandomänen sind in spezieller Weise zur Initiation von Signaltransduktionskaskaden geeignet. Komplexbildung, die Generierung einer Plattform für Signaltransduktion und ihrer Eigenschaft präferenziell in Vesikelform, sog. Exosomen, von der Tumorzelle freigesetzt zu werden, prädestinieren Tetraspanine für eine zentrale Rolle bei allen Schritten der Metastasierungskaskade. In Anbetracht dieser multiplen Involvierung der Tetraspanine in den Metastasierungsprozess und eines sich in den letzten Jahren zunehmend experimentell festigenden Konzepts zum Prozess der Metastasierung sind diesem kurzen Überblick über die Funktion von Tetraspaninen, die aus heutiger Sicht zentralen Elemente der Tumorprogression, reversible Differenzierung von Tumorstammzellen und Bedeutung der Tumor-Wirt-Beziehung, vorangestellt.

Abstract

Tumors of the gastrointestinal tract - gastric, colorectal, pancreatic and liver tumors - account for over 50 % of cancer worldwide. The 5-year survival rate varies from > 50 % in colorectal to < 1 % in pancreatic cancer. The high cancer death rate strikingly correlates with the high metastasizing capacity of most gastrointestinal tumors. Therefore and because during the last decade several important hypotheses on metastasis formation could be settled on solid experimental ground, this review will first provide a brief outline on the currently most accepted view of tumor progression and then discuss whether and how the rather new family of tetraspanin molecules might contribute to cancer progression. Notably, some members of this family, in particular, CD82/KAI1 are known as metastasis suppressor genes, while others like CD151 and CO-029 are supposed to promote metastasis formation. The underlying mechanisms are beginning to become unraveled. Tetraspanins assemble complexes of different tetraspanins, integrins and additional transmembrane molecules in microdomains that serve as signaling platform. By creating proximity, tetraspanins modulate functional activity of the associating molecules. In addition, tetraspanins actively contribute to the intracellular traffic of the associating molecules that includes vesicular budding and formation of exosomes that are particularly rich in tetraspanins. Accordingly, the association of certain tetraspanins with the metastatic phenotype as well as the definition of other tetraspanins as metastasis suppressor genes has to be viewed from the perspective of molecular complexes rather than the individual tetraspanin.

Schlüsselwörter

Tumorprogression - Angiogenese - Tetraspanine - CO-029 - CD82/KAI1

Key words

Tumor progression - angiogenesis - tetraspanins - CO-029 - CD82/KAI1

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