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

Abstract

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 LTα1β2 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.

Elevated NIBP/TRAPPC9 mediates tumorigenesis of cancer cells through NFκB signaling

“…TNFα is deemed consistently to stimulate NFκB activation in different cancer cells. LT-α1β2 is also well known to stimulate NFκB activation in most cells [54-56]. Interestingly, we found that IL-1β, a common stimulator for NFκB signaling in most cells, fails to activate NFκB in MDA-MB-231 cells other than in HCT116 cells.…”

Lymphotoxin, NF-ĸB, and Cancer: The Dark Side of Cytokines

“…In further studies, it was shown that LTβR ligands LT and LIGHT expressed by tumor infiltrating lymphocytes lead to upregulation of the proangiogenic chemokine CXCL-2 in fibrosarcoma cells [100]. Therefore, LT also plays a tumor-intrinsic role for organization of tumor tissue during tumor development.…”

Mouse β-Defensin 14 (Defb14) Promotes Tumor Growth by Inducing Angiogenesis in a CCR6-Dependent Manner

“…The TNFR1:Ig, the mBD14:Ig, and the LTbR:Ig expression constructs were generated by insertion of the corresponding cDNA encoding for the extracellular domain of the TNFR1, the mature mBD14, or the soluble form of the LTbR into the Signal pIg plus vector (R&D Systems, WiesbadenNordenstadt, Germany), as described earlier (8,16,17). Stable transfectants expressing the TNFR1:Ig, the mBD14:Ig, or the LTbR:Ig fusion protein were prepared by transfection of BFS-1 cells with the corresponding expression construct using DOTAP (Roche Diagnostics, Mannheim, Germany), following the manufacturer's instructions.…”

“…In earlier studies, we have shown that LTbR activation on BFS-1 tumor cells by ligand-expressing cells like activated B cells is a prerequisite for CXCL2 expression in BFS-1 tumor cells and subsequently tumor growth (17). Thus, we used the soluble LTbR:Ig fusion protein as inhibitor for LTbR activation.…”

“…LTbR activation on fibrosarcoma cells by LTa 1 b 2 , expressed on host cell-derived lymphocytes, induced the expression of proangiogenic CXCL2 (MIP-2). Prevention of LTbR activation inhibited tumor angiogenesis and neovascularization and resulted in tumor growth arrest (16,17).…”