Lymphotoxin-β receptor activation by lymphotoxin-α1β2 and LIGHT promotes tumor growth in an NFκB-dependent manner

Lymphotoxin beta receptor (LT beta R) 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 LT beta R, namely LT alpha(1)beta(2) and LIGHT, are involved in the activation of LT beta R in solid fibrosarcomas. To identify whether the lymphocyte population is involved in the activation of LT beta R in these fibrosarcoma tumors, we used conditional LT beta-deficient mice that specifically lack LT beta expression either on T cells (T-LT beta(-/-)) or on B cells (B-LT beta(-/-)). 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 LT beta R in these tumors. Tumor growth was also reduced in LIGHT-deficient mice, suggesting a contribution of this ligand to the activation of LT beta R in BFS-1 fibrosarcomas. LT beta R signaling can involve I kappa B alpha and/or NF kappa B-inducing kinase (NIK) for subsequent NF kappa B activation in different types of cells. Expression of a dominant negative form of I kappa B alpha or of a dominant negative mutant of NIK resulted in decreased activation of NF kappa B signaling and reduced expression of pro-angiogenic CXCL2 in vitro. Moreover, expression of dominant negative form of NIK or an I kappa B alpha repressor in these fibrosarcoma cells resulted in reduced solid tumor growth in vivo, suggesting that both I kappa B alpha and NIK are involved in pro-angiogenic signaling after LT beta R activation. Our data support the idea that the ablation of LT beta R signaling should be considered for cancer treatment.