Abstract
The cytokines lymphotoxin (LT) α, β and their receptor (LTβR) belong to the tumor necrosis factor (TNF) superfamily, whose founder—TNFα—was initially discovered due to its tumor necrotizing activity. LTβR signaling serves pleiotropic functions including the control of lymphoid organ development, support of efficient immune responses against pathogens due to maintenance of intact lymphoid structures, induction of tertiary lymphoid organs, liver regeneration or control of lipid homeostasis. Signaling through LTβR comprises the noncanonical/canonical nuclear factor-κB (NF-κB) pathways thus inducing chemokine, cytokine or adhesion molecule expression, cell proliferation and cell survival. Blocking LTβR signaling or Fcγ-receptor mediated immunoablation of LT-expressing cells was demonstrated to be beneficial in various infectious or noninfectious inflammatory or autoimmune disorders. Only recently, LTβR signaling was shown to initiate inflammation-induced carcinogenesis, to influence primary tumorigenesis and to control reemergence of carcinoma in various cancer models through distinct mechanisms. Indeed, LTβR signaling inhibition has already been used as efficient anti-inflammatory, anti-cancer therapy in some experimental models. Here, we review the pleiotropic functions attributed to LT, the effects of its deregulation and extensively discuss the recent literature on LT's link to carcinogenesis.
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Acknowledgements
We thank Dr Tracy O’Connor, Dr Barbara Stecher, Jay Tracy and Lukas Frick for critically reading this paper. MH was supported by grants of the Oncosuisse foundation (OCS 02113-08-2007), the Novartis Stiftung für Biologisch-Medizinische Forschung (Nr. 09C62), the ‘Stiftung zur Schweizerischen Krebsbekämpfung’, the Helmholtz-foundation, the research foundation at the Medical Faculty Zurich, the Julius-Müller foundation and the ‘Kurt und Senta Hermann Stiftung’. MJW was supported by a grant of the Roche Research Foundation. MH is a fellow of the Professor Dr Max Cloëtta foundation.
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Dr Mathias Heikenwälder is in the process of designing a clinical trial using LTBR-Ig (baminercept) in hepatitis C virus-infected patients, which would be partially funded by Biogen Idec. The planned trial is not yet approved. Dr Nicolas Zeller, Monika Wolf and Gitta Seleznik declare no conflict of interest.
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Wolf, M., Seleznik, G., Zeller, N. et al. The unexpected role of lymphotoxin β receptor signaling in carcinogenesis: from lymphoid tissue formation to liver and prostate cancer development. Oncogene 29, 5006–5018 (2010). https://doi.org/10.1038/onc.2010.260
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Salivary factor LTRIN from Aedes aegypti facilitates the transmission of Zika virus by interfering with the lymphotoxin-β receptor
Nature Immunology (2018)
