Context-dependent roles for lymphotoxin-β receptor signaling in cancer development

Abstract

The LTα1β2 and LIGHT TNF superfamily cytokines exert pleiotropic physiological functions through the activation of their cognate lymphotoxin-β receptor (LTβR). Interestingly, since the discovery of these proteins, accumulating evidence has pinpointed a role for LTβR signaling in carcinogenesis. Early studies have shown a potential anti-tumoral role in a subset of solid cancers either by triggering apoptosis in malignant cells or by eliciting an anti-tumor immune response. However, more recent studies provided robust evidence that LTβR signaling is also involved in diverse cell-intrinsic and microenvironment-dependent pro-oncogenic mechanisms, affecting several solid and hematological malignancies. Consequently, the usefulness of LTβR signaling axis blockade has been investigated as a potential therapeutic approach for cancer. Considering the seemingly opposite roles of LTβR signaling in diverse cancer types and their key implications for therapy, we here extensively review the different mechanisms by which LTβR activation affects carcinogenesis, focusing on the diverse contexts and different models assessed.

TNF-driven adaptive response mediates resistance to EGFR inhibition in lung cancer

“…Next, we investigated whether individual components of the NF-κB target signature genes play a key role in mediating resistance to EGFR inhibition. Lymphotoxin-β (LTB, TNFC), a member of the TNF superfamily, has a known role in cancer development, including in solid tumors (46), and may play an important role in mediating resistance to cetuximab in head and neck cancer (47). Lymphotoxin-β may trigger multiple survival mechanisms, including activation of NF-κB (46), acceleration of Akt-induced cancer (48), and enhanced EGFR signaling (47).…”

Clathrin- and dynamin-dependent endocytosis limits canonical NF-κB signaling triggered by lymphotoxin β receptor

“…Although LTβR was shown to trigger different signaling pathways [ 10 – 14 ], the kinetics of their activation by LTβR ligands was not studied systematically. To address this issue, we analyzed the status of selected pathways in A549 cells stimulated for various time periods with Ago, LTα1β2 or LIGHT.…”

“…It controls the development and maintenance of secondary lymphoid organs: lymph nodes [ 1 ] and Peyer’s patches [ 2 ], and immune cell development [ 3 – 6 ]. LTβR is constitutively and ubiquitously expressed, with an exception of T and B lymphocytes [ 7 , 8 ], which in turn are the source of its two ligands: lymphotoxin α1β2 (LTα1β2) and LIGHT [ 9 , 10 ].…”

“…Ligand binding by LTβR activates signaling cascades, leading to NF-κB- and AP-1-dependent transcription [ 10 – 15 ]. The best characterized in this context is NF-κB signaling, operating via two branches: the canonical and non-canonical ones [ 11 , 12 , 15 ].…”

“…While there are many reports on tyrosine kinase receptors (RTKs) and G protein-coupled receptors (GPCRs), showing the link between endocytosis and signaling [ 23 , 54 , 55 ], the knowledge on such regulation for cytokine receptors is limited [ 22 ]. Most of the studies on LTβR focus on its role in development and maintenance of immune system [ 56 , 57 ], as well as its contribution to the progress of different diseases [ 10 , 58 ]. In contrast, there are only a few reports on the cell biology of LTβR.…”