| Autor: |
Tobias Lange, Ursula Valentiner, Daniel Wicklein, Hanna Maar, Vera Labitzky, Ann-Kristin Ahlers, Sarah Starzonek, Sandra Genduso, Lisa Staffeldt, Carolin Pahlow, Anna-Maria Dück, Christine Stürken, Anke Baranowsky, Alexander T. Bauer, Etmar Bulk, Albrecht Schwab, Kristoffer Riecken, Christian Börnchen, Rainer Kiefmann, Valsamma Abraham, Horace M. DeLisser, Timo Gemoll, Jens K. Habermann, Andreas Block, Klaus Pantel, Udo Schumacher |
| Rok vydání: |
2021 |
| Předmět: |
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| Zdroj: |
Molecular therapy : the journal of the American Society of Gene Therapy. 30(4) |
| ISSN: |
1525-0024 |
| Popis: |
Extravasation of circulating tumor cells (CTCs) is critical for metastasis and is initiated by adhesive interactions between glycoligands on CTCs and E-selectin on endothelia. Here, we show that the clinically approved proteasome inhibitor bortezomib (BZM; Velcade) counteracts the cytokine-dependent induction of E-selectin in the lung mediated by the primary tumor, thereby impairing endothelial adhesion and thus spontaneous lung metastasis in vivo. However, the efficacy of BZM crucially depends on the tumor cells' E-selectin ligands, which determine distinct adhesion patterns. The canonical ligands sialyl-Lewis A (sLeA) and sLeX mediate particularly high-affinity E-selectin binding so that the incomplete E-selectin-reducing effect of BZM is not sufficient to disrupt adhesion or metastasis. In contrast, tumor cells lacking sLeA/X nevertheless bind E-selectin, but with low affinity, so that adhesion and lung metastasis are significantly diminished. Such low-affinity E-selectin ligands apparently consist of sialylated MGAT5 products on CD44. BZM no longer has anti-metastatic activity after CD44 knockdown in sLeA/X-negative tumor cells or E-selectin knockout in mice. sLeA/X can be determined by immunohistochemistry in cancer samples, which might aid patient stratification. These data suggest that BZM might act as a drug for inhibiting extravasation and thus distant metastasis formation in malignancies expressing low-affinity E-selectin ligands. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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