Mechanisms of metastasis

Bis eine Primärtumorzelle ihr Ziel erreicht, eine klinisch erfassbare Metastase zu bilden, muss sie eine heute immer besser definierte Kaskade von Hindernissen überspringen. Sie tut dies durch die Akkumulation von Mutationen infolge einer größeren Genominstabilität. Nicht wenige dieser Mutationen betreffen Prozesse, mit denen die metastasierende Zelle ihre Gewebeumgebung beeinflusst, um ihre Invasivitätschancen vom Primärtumor weg und ihre Wachstumschancen im Zielorgan zu erhöhen. Neue therapeutische Ansätze sind auf die pharmakologische Unterbindung der Blutzufuhr für klinisch noch nicht erfassbare Mikrometastasen ausgerichtet. Tierexperimentelle Konzepte und Erfolge in diesem Zusammenhang müssen nun aber vorerst über Phase-II-Studien solider verankert werden.

Until a primary tumor can successfully produce clinically relevant metastases, the seed cells have to go through a series of stepwise changes (mutations) which have to overcome a sizeable cascade of obstacles. Some of the experimentally proven and clinically suspected changes involve cell surface adhesion, general and local growth factor responsiveness, protease and glycosidase production, motility and deformability. In addition to this tumor cell centered view, one begins to broaden the vision to include changes in the interactions between the tumor cell and its immediate environment. In this context it turns out that the tumor cell seems to learn how to entice neighboring cells and tissues to support its progress with several different responses: extracellular matrix degrading enzymes, growth factors in the target organ, angiogenesis etc. The multitude of phenotype variants is due to genome instability, which is higher in metastatic cells than in primary tumor cells. Recently, it could be shown that even chemotherapy drug resistance is increased in the metastatic organ surrounding (lung) compared to non-metastatic organ targets. The role of the immunsystem for organ specific metastasis is – if anything – less clear than earlier assumed. Important for the surgeon is the fact that his efforts with the primary tumor could become yet even more successful if the dormant or micrometastases could be abolished. New therapeutic approaches include specific inhibitors of angiogenesis receptors (tyrosine kinase inhibitors). Recently, it was found that continuous low dose chemotherapy together with antiinflammatory agents which block endothelial cell migration and growth prevent not only tumor growth, but abolish micrometastases efficently in animals. Clinical phase II studies are underway. This, as so many other promising starts in cancer therapy, needs, however, solid confirmation on a very expanded scale before any hopes can be raised.