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Transforming Growth Factor β Released by Platelets Primes Macrophage Activation and Extracellular Trap Formation, Thereby Influencing Breast Cancer Growth in Mice
ISTH Academy. Mammadova-Bach E. Jul 10, 2019; 274035; OC 79.4
Dr. Elmina Mammadova-Bach
Dr. Elmina Mammadova-Bach
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OC 79.4

Transforming Growth Factor β Released by Platelets Primes Macrophage Activation and Extracellular Trap Formation, Thereby Influencing Breast Cancer Growth in Mice

E. Mammadova-Bach1,2, J. Gil-Pulido1,3, I. Jorgacevic1, S. Beck1,2, K. Remer1,2, A. Braun1,2, S.I. Abrams4, A. Zernecke1, B. Nieswandt1,2
1Institute of Experimental Biomedicine, University Hospital Würzburg, Würzburg, Germany, 2Rudolf Virchow Center, University of Würzburg, Würzburg, Germany, 3Institute of Molecular Biology, Mainz, Germany, 4Department of Immunology Roswell Park Comprehensive Cancer Center, Buffalo, United States

Main Topic: Platelets and Megakaryocytes
Category: Platelet Function & Interactions

Background: Leukocytes release their chromatin fibers, referred to neutrophil extracellular traps (NETs), which are composed by DNA, histones and granule content. NET formation facilitates tumor cell aggressiveness in the context of systemic inflammation. Earlier, it has been shown that platelets could promote NET formation during bacterial infections. Recent studies indicated that activated platelets may also induce monocyte/macrophage-dependent extracellular trap (MET) formation, a process termed as METosis, thereby exacerbating organ injury and inflammation. However, the role of activated platelets in METosis during tumor growth has not been investigated.
Aims: We examined the role of platelets in the formation of METs during breast cancer growth.
Methods: Breast tumors were induced by orthotopic injection of two different breast cancer cell lines called AT-3 and E0771. Tumor growth was analysed in wild-type (WT) mice and megakaryocyte/platelet specific TGFß-knockout mice (TGFßfl/fl-PF4-Cre) which were treated with
(i) DNAse I,
(ii) macrophage-depleting chlodronate liposomes,
(iii) platelet- and
(iv) neutrophil-depleting antibodies.
Infiltration of immune cells into the growing tumors was followed by immunofluorescence confocal microscopy and flow cytometry.
Results: We show that macrophage depletion decreased tumor volume in WT mice to a similar extent as DNAse I treatment. In contrast, depletion of neutrophils did not alter tumor growth in WT mice, indicating that neither neutrophils, nor NETs are critical for breast cancer growth. Moreover, we found that platelet depletion or TGFß deficiency in platelets inhibited METosis. Depletion of macrophages and MET formation attenuated tumor growth and this process was strongly dependent on TGFß released by activated platelets.
Conclusions: Platelet-derived TGFß enhances tumor growth by priming macrophage activation and METosis. Our findings reveal that inhibition of TGFß released by activated platelets may represent a new therapeutic strategy to decrease breast cancer growth by interfering with pro-tumorigenic macrophage function.

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