Cooperative function of CCR7 and lymphotoxin in the formation of a lymphoma-permissive niche within murine secondary lymphoid organs.
Blood
; 118(4): 1020-33, 2011 Jul 28.
Article
em En
| MEDLINE
| ID: mdl-21586747
ABSTRACT
Lymphoma cell survival and progression are putatively dependent on a specific microanatomic localization 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 Eµ-Myc transgenic mouse model, we show that the chemokine receptor CCR7 regulates Eµ-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 with CCR7-deficient lymphoma cells, which were excluded from this zone. Within the niche, lymphoma cells stimulated a reciprocal cross-talk with gp38(+) fibroblastic reticular cells. This reciprocal cooperation program was mediated by lymphoma B cell-presented lymphotoxin, which acted on lymphotoxin-ß-receptor-bearing stromal cells followed by alteration of stromal cellular composition. Cross-talk inhibition by lymphotoxin-α deletion and using a lymphotoxin-ß 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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Linfoma de Células B
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Linfotoxina-alfa
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Receptores CCR7
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Microambiente Tumoral
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Tecido Linfoide
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Ano de publicação:
2011
Tipo de documento:
Article