Lymphotoxin-β receptor activation by lymphotoxin-α1β2 and LIGHT promotes tumor growth in an NFκB-dependent manner
| Autor: | Barbara Daller, Werner Müsch, Johann Röhrl, Sergei A. Nedospasov, Daniela N. Männel, Alexei V. Tumanov, Thomas Hehlgans, Wulf Schneider-Brachert |
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| Rok vydání: | 2011 |
| Předmět: |
Lymphotoxin-beta
Tumor Necrosis Factor Ligand Superfamily Member 14 Cancer Research Angiogenesis Fibrosarcoma T-Lymphocytes Blotting Western Chemokine CXCL2 Population Apoptosis Biology Mice Lymphotoxin beta Receptor medicine Animals RNA Messenger education Cells Cultured Cell Proliferation Mice Knockout B-Lymphocytes education.field_of_study Reverse Transcriptase Polymerase Chain Reaction Tumor Necrosis Factor-alpha Cell growth Lymphotoxin alpha1 beta2 Heterotrimer NF-kappa B Flow Cytometry medicine.disease Mice Inbred C57BL IκBα Lymphotoxin Oncology Cancer research Female Signal transduction Lymphotoxin beta receptor Signal Transduction |
| Zdroj: | International Journal of Cancer. 128:1363-1370 |
| ISSN: | 0020-7136 |
| Popis: | Lymphotoxin beta receptor (LTβR) activation on mouse fibrosarcoma cells (BFS-1) results in enhanced solid tumor growth paralleled by increased angiogenesis induced by the expression of pro-angiogenic CXCL2. In our study, we demonstrate that both functional ligands of the LTβR, namely LTα(1) β(2) and LIGHT, are involved in the activation of LTβR in solid fibrosarcomas. To identify whether the lymphocyte population is involved in the activation of LTβR in these fibrosarcoma tumors, we used conditional LTβ-deficient mice that specifically lack LTβ expression either on T cells (T-LTβ(-/-)) or on B cells (B-LTβ(-/-)). Solid tumor growth was reduced in both mouse strains when compared to tumor growth in wild-type mice, indicating the participation of both T and B host lymphocytes in the activation of LTβR in these tumors. Tumor growth was also reduced in LIGHT-deficient mice, suggesting a contribution of this ligand to the activation of LTβR in BFS-1 fibrosarcomas. LTβR signaling can involve IκBα and/or NFκB-inducing kinase (NIK) for subsequent NFκB activation in different types of cells. Expression of a dominant negative form of IκBα or of a dominant negative mutant of NIK resulted in decreased activation of NFκB signaling and reduced expression of pro-angiogenic CXCL2 in vitro. Moreover, expression of dominant negative form of NIK or an IκBα repressor in these fibrosarcoma cells resulted in reduced solid tumor growth in vivo, suggesting that both IκBα and NIK are involved in pro-angiogenic signaling after LTβR activation. Our data support the idea that the ablation of LTβR signaling should be considered for cancer treatment. |
| Databáze: | OpenAIRE |
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