Bone marrow niche-derived extracellular matrix-degrading enzymes influence the progression of B-cell acute lymphoblastic leukemia
| Autor: | Markus Metzler, Barbara Burroni, Costanza Zanetti, Parimala Sonika Godavarthy, Véronique Maguer-Satta, Michaela Fontenay, Franck E. Nicolini, Jakob Pfeiffer, Daniela S. Krause, Rahul Kumar, Valentina R. Minciacchi, Sylvain Lefort, Divij Verma |
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| Přispěvatelé: | Institute for Tumor Biology and Experimental Therapy [Frankfurt, Germany], University Hospital Erlangen [Germany], Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Léon Bérard [Lyon], Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Descartes - Paris 5 (UPD5), Johann Wolfgang Goethe University, Goethe-Universität Frankfurt am Main, Goethe-University Frankfurt am Main, German Cancer Consortium [Heidelberg] (DKTK), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM) |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Cancer microenvironment
Cancer Research [SDV]Life Sciences [q-bio] Article Extracellular matrix Mice 03 medical and health sciences 0302 clinical medicine Bone Marrow Precursor B-Cell Lymphoblastic Leukemia-Lymphoma Tumor Microenvironment medicine Animals Neoplasm Invasiveness Receptor 030304 developmental biology Mice Knockout 0303 health sciences Gene knockdown Tumor Necrosis Factor-alpha Chemistry Mesenchymal stem cell Hematology medicine.disease Extracellular Matrix 3. Good health Mice Inbred C57BL Leukemia medicine.anatomical_structure Matrix Metalloproteinase 9 Oncology Preclinical research Tumor progression 030220 oncology & carcinogenesis Disease Progression Cancer research Tumor necrosis factor alpha Bone marrow |
| Zdroj: | Leukemia Leukemia, Nature Publishing Group: Open Access Hybrid Model Option B, 2020, 34 (6), pp.1540-1552. ⟨10.1038/s41375-019-0674-7⟩ |
| ISSN: | 0887-6924 1476-5551 |
| Popis: | Specific and reciprocal interactions with the bone marrow microenvironment (BMM) govern the course of hematological malignancies. Matrix metalloproteinase-9 (MMP-9), secreted by leukemia cells, facilitates tumor progression via remodeling of the extracellular matrix (ECM) of the BMM. Hypothesizing that leukemias may instruct the BMM to degrade the ECM, we show, that MMP-9-deficiency in the BMM prolongs survival of mice with BCR-ABL1-induced B-cell acute lymphoblastic leukemia (B-ALL) compared with controls and reduces leukemia-initiating cells. MMP-9-deficiency in the BMM leads to reduced degradation of proteins of the ECM and reduced invasion of B-ALL. Using various in vivo and in vitro assays, as well as recipient mice deficient for the receptor for tumor necrosis factor (TNF) α (TNFR1) we demonstrate that B-ALL cells induce MMP-9-expression in mesenchymal stem cells (MSC) and possibly other cells of the BMM via a release of TNFα. MMP-9-expression in MSC is mediated by activation of nuclear factor kappa B (NF-κB) downstream of TNFR1. Consistently, knockdown of TNF-α in B-ALL-initiating cells or pharmacological inhibition of MMP-9 led to significant prolongation of survival in mice with B-ALL. In summary, leukemia cell-derived Tnfα induced MMP-9-expression by the BMM promoting B-ALL progression. Inhibition of MMP-9 may act as an adjunct to existing therapies. |
| Databáze: | OpenAIRE |
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