Integrin regulation by tissue factor promotes cancer stemness and metastatic dissemination in breast cancer.

Autor: Ünlü B; Einthoven Laboratory for Experimental Vascular Medicine, Department of Internal Medicine, Leiden University Medical Center, Leiden, The Netherlands., Kocatürk B; Einthoven Laboratory for Experimental Vascular Medicine, Department of Internal Medicine, Leiden University Medical Center, Leiden, The Netherlands., Rondon AMR; Einthoven Laboratory for Experimental Vascular Medicine, Department of Internal Medicine, Leiden University Medical Center, Leiden, The Netherlands., Lewis CS; Division of Hematology/Oncology, Department of Internal Medicine, College of Medicine University of Cincinnati, Cincinnati, OH, USA., Swier N; Einthoven Laboratory for Experimental Vascular Medicine, Department of Internal Medicine, Leiden University Medical Center, Leiden, The Netherlands., van den Akker RFP; Einthoven Laboratory for Experimental Vascular Medicine, Department of Internal Medicine, Leiden University Medical Center, Leiden, The Netherlands., Krijgsman D; Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands., Noordhoek I; Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands., Blok EJ; Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands., Bogdanov VY; Division of Hematology/Oncology, Department of Internal Medicine, College of Medicine University of Cincinnati, Cincinnati, OH, USA., Ruf W; Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, USA.; Center for Thrombosis and Hemostasis, Johannes Gutenberg University Medical Center, Mainz, Germany., Kuppen PJK; Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands., Versteeg HH; Einthoven Laboratory for Experimental Vascular Medicine, Department of Internal Medicine, Leiden University Medical Center, Leiden, The Netherlands. h.h.versteeg@lumc.nl.
Jazyk: angličtina
Zdroj: Oncogene [Oncogene] 2022 Nov; Vol. 41 (48), pp. 5176-5185. Date of Electronic Publication: 2022 Oct 21.
DOI: 10.1038/s41388-022-02511-7
Abstrakt: Tissue Factor (TF) is the initiator of blood coagulation but also functions as a signal transduction receptor. TF expression in breast cancer is associated with higher tumor grade, metastasis and poor survival. The role of TF signaling on the early phases of metastasis has never been addressed. Here, we show an association between TF expression and metastasis as well as cancer stemness in 574 breast cancer patients. In preclinical models, blockade of TF signaling inhibited metastasis tenfold independent of primary tumor growth. TF blockade caused a reduction in epithelial-to-mesenchymal-transition, cancer stemness and expression of the pro-metastatic markers Slug and SOX9 in several breast cancer cell lines and in ex vivo cultured tumor cells. Mechanistically, TF forms a complex with β1-integrin leading to inactivation of β1-integrin. Inhibition of TF signaling induces a shift in TF-binding from α3β1-integrin to α6β4 and dictates FAK recruitment, leading to reduced epithelial-to-mesenchymal-transition and tumor cell differentiation. In conclusion, TF signaling inhibition leads to reduced pro-metastatic transcriptional programs, and a subsequent integrin β1 and β4-dependent reduction in metastasic dissemination.
(© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
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