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Cooperative function of CCR7 and lymphotoxin in the formation of a lymphoma-permissive niche within murine secondary lymphoid organs

Item Type:Article
Title:Cooperative function of CCR7 and lymphotoxin in the formation of a lymphoma-permissive niche within murine secondary lymphoid organs
Creators Name:Rehm, A. and Mensen, A. and Schradi, K. and Gerlach, K. and Wittstock, S. and Winter, S. and Buechner, G. and Doerken, B. and Lipp, M. and Höpken, U.E.
Abstract:Lymphoma cell survival and progression is putatively dependent on a specific microanatomical localisation within secondary lymphoid organs. Despite compelling data correlating homeostatic chemokine receptor expression and human lymphoma pathogenesis, genetic models that either mimic lymphoma dissemination or dissect a crosstalk of lymphoma and stromal cells are missing. Applying the genetically tractable Emu-Myc transgenic mouse model, we show that the chemokine receptor CCR7 regulates Emu-Myc lymphoma homing to lymph nodes and distinctive microanatomic sites of the spleen. CCR7-controlled access of lymphoma cells to the splenic T cell zone led to a significant survival advantage compared to CCR7-deficient lymphoma cells which were excluded from this zone. Within the niche, lymphoma cells stimulated a reciprocal crosstalk with gp38(+) fibroblastic reticular cells. This reciprocal cooperation program was mediated by lymphoma B cell-presented lymphotoxin which acted on lymphotoxin beta receptor-bearing stromal cells followed by alteration of stromal cellular composition. Crosstalk inhibition by lymphotoxin alpha deletion and by employing a lymphotoxin beta receptor-immunoglobulin fusion protein impaired lymphoma growth. Thus, abrogation of CCR7-governed migration and of sustained lymphotoxin signaling could provide new targets in lymphoma therapy.
Keywords:Adoptive Transfer, B-Cell Lymphoma, CCR7 Receptors, Cell Movement, Cell Separation, Confocal Microscopy, Disease Progression, Flow Cytometry, Fluorescent Antibody Technique, Immunohistochemistry, Inbred C57BL Mice, In Situ Nick-End Labeling, Lymphoid Tissue, Lymphotoxin-alpha, Lymphocyte Homing Receptors, Receptor Cross-Talk, Reverse Transcriptase Polymerase Chain Reaction, Transgenic Mice, Transfection, Tumor Microenvironment, Animals, Mice
Publisher:American Society of Hematology
Page Range:1020-1033
Date:28 July 2011
Official Publication:https://doi.org/10.1182/blood-2010-11-321265
PubMed:View item in PubMed

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