Uhl, Bernd and Mittmann, Laura and Dominik, Julian and Hennel, Roman and Smiljanov, Bojan and Haring, Florian and Schaubaecher, Johanna and Braun, Constanze and Padovan, Lena and Pick, Robert and Canis, Martin and Schulz, Christian and Mack, Matthias and Gutjahr, Ewgenija and Sinn, Peter and Heil, Joerg and Steiger, Katja and Kanse, Sandip M. and Weichert, Wilko and Sperandio, Markus and Lauber, Kirsten and Krombach, Fritz and Reichel, Christoph A. (2021) uPA-PAI-1 heteromerization promotes breast cancer progression by attracting tumorigenic neutrophils. EMBO MOLECULAR MEDICINE, 13 (6): e13110. ISSN 1757-4676, 1757-4684
Full text not available from this repository. (Request a copy)Abstract
High intratumoral levels of urokinase-type plasminogen activator (uPA)-plasminogen activator inhibitor-1 (PAI-1) heteromers predict impaired survival and treatment response in early breast cancer. The pathogenetic role of this protein complex remains obscure. Here, we demonstrate that heteromerization of uPA and PAI-1 multiplies the potential of the single proteins to attract pro-tumorigenic neutrophils. To this end, tumor-released uPA-PAI-1 utilizes very low-density lipoprotein receptor and mitogen-activated protein kinases to initiate a pro-inflammatory program in perivascular macrophages. This enforces neutrophil trafficking to cancerous lesions and skews these immune cells toward a pro-tumorigenic phenotype, thus supporting tumor growth and metastasis. Blockade of uPA-PAI-1 heteromerization by a novel small-molecule inhibitor interfered with these events and effectively prevented tumor progression. Our findings identify a therapeutically targetable, hitherto unknown interplay between hemostasis and innate immunity that drives breast cancer progression. As a personalized immunotherapeutic strategy, blockade of uPA-PAI-1 heteromerization might be particularly beneficial for patients with highly aggressive uPA-PAI-1(high) tumors.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | PLASMINOGEN-ACTIVATOR INHIBITOR-1; ADJUVANT CHEMOTHERAPY; BLOOD-VESSELS; HIGH-RISK; UROKINASE; RECEPTOR; TYPE-1; COMPLEX; PAI-1; THERAPY; biomarker; breast cancer; fibrinolysis; innate immunity; neutrophils |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Innere Medizin II |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 23 Sep 2022 05:09 |
| Last Modified: | 23 Sep 2022 05:09 |
| URI: | https://pred.uni-regensburg.de/id/eprint/47884 |
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