cancers Review Dual Role of TNF and LTα in Carcinogenesis as Implicated by Studies in Mice Ekaterina O. Gubernatorova 1,2,*, Almina I. Polinova 1,2, Mikhail M. Petropavlovskiy 1,2, Olga A. Namakanova 1,2, Alexandra D. Medvedovskaya 1,2, Ruslan V. Zvartsev 1,3, Georgij B. Telegin 4, Marina S. Drutskaya 1,3,* and Sergei A. Nedospasov 1,2,3,5,* 1 Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia; [email protected] (A.I.P.); [email protected] (M.M.P.); [email protected] (O.A.N.); [email protected] (A.D.M.); [email protected] (R.V.Z.) 2 Department of Immunology, Faculty of Biology, Lomonosov Moscow State University, 119234 Moscow, Russia 3 Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia 4 Branch of Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences (BIBCh, RAS), 142290 Pushchino, Russia; [email protected] 5 Sirius University of Science and Technology, Federal Territory Sirius, 354340 Krasnodarsky Krai, Russia * Correspondence: [email protected] (E.O.G.); [email protected] (M.S.D.); [email protected] (S.A.N.) Simple Summary: Tumor necrosis factor (TNF) and its closely related cytokine, lymphotoxin alpha (LTα), are part of the TNF superfamily and exert their functions via both overlapping and non- Citation: Gubernatorova, E.O.; redundant signaling pathways. Reported pro- and antitumorigenic effects of TNF and lymphotoxin Polinova, A.I.; Petropavlovskiy, M.M.; are often context-dependent and may be contingent on a particular experimental approach, such Namakanova, O.A.; Medvedovskaya, as transplantable and chemically induced tumor models; tissue and organ specificity; types of cells A.D.; Zvartsev, R.V.; Telegin, G.B.; producing these cytokines or responding to them; and the genotype and genetic background of mice. Drutskaya, M.S.; Nedospasov, S.A. Here, we review the mechanisms of TNF/LTα involvement in cancer promotion and suppression Dual Role of TNF and LTα in Carcinogenesis as Implicated by as studied in mouse models. We also discuss the impact of microbiota on tumor development and Studies in Mice. Cancers 2021, 13, manipulations of the TNF/LT system, which may be effective as anti-cancer therapy. 1775. https://doi.org/10.3390/ cancers13081775 Abstract: Tumor necrosis factor (TNF) and lymphotoxin alpha (LTα) are two related cytokines from the TNF superfamily, yet they mediate their functions in soluble and membrane-bound forms via Academic Editors: Heinrich Korner overlapping, as well as distinct, molecular pathways. Their genes are encoded within the major and Lisa M. Sedger histocompatibility complex class III cluster in close proximity to each other. TNF is involved in host defense, maintenance of lymphoid tissues, regulation of cell death and survival, and antiviral and Received: 18 March 2021 antibacterial responses. LTα, known for some time as TNFβ, has pleiotropic functions including Accepted: 2 April 2021 control of lymphoid tissue development and homeostasis cross talk between lymphocytes and their Published: 8 April 2021 environment, as well as lymphoid tissue neogenesis with formation of lymphoid follicles outside the lymph nodes. Along with their homeostatic functions, deregulation of these two cytokines may be Publisher’s Note: MDPI stays neutral associated with initiation and progression of chronic inflammation, autoimmunity, and tumorigenesis. with regard to jurisdictional claims in In this review, we summarize the current state of knowledge concerning TNF/LTα functions in tumor published maps and institutional affil- iations. promotion and suppression, with the focus on the recently uncovered significance of host–microbiota interplay in cancer development that may explain some earlier controversial results. Keywords: tumor necrosis factor; lymphotoxin alpha; TNFR2; LTβR; cancer; microbiota; mouse models Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and 1. Introduction conditions of the Creative Commons Attribution (CC BY) license (https:// Tumor necrosis factor (TNF) and lymphotoxin alpha (LTα) exist as soluble homotrimers creativecommons.org/licenses/by/ and interact with TNF receptors (p55 TNFR1 and p75 TNFR2). LTα homotrimer also binds 4.0/). to herpes virus entry mediator (HVEM) as does LIGHT (TNFSF14), another member of Cancers 2021, 13, 1775. https://doi.org/10.3390/cancers13081775 https://www.mdpi.com/journal/cancers Cancers 2021, 13, x FOR PEER REVIEW 2 of 27 1. Introduction Cancers 2021, 13, 1775 Tumor necrosis factor (TNF) and lymphotoxin alpha (LTα) exist as soluble homotri2 of 25‐ mers and interact with TNF receptors (p55 TNFR1 and p75 TNFR2). LTα homotrimer also binds to herpes virus entry mediator (HVEM) as does LIGHT (TNFSF14), another member ofthe the TNF TNF superfamily superfamily (Figure (Figure1). In1). addition In addition to their to their soluble soluble forms, forms, TNF TNF homotrimer homotrimer func- functionstions as a as transmembrane a transmembrane molecule molecule (tmTNF), (tmTNF), whereas whereas LT LTα α homotrimerhomotrimer exists exists only only in in a asoluble soluble form, form, but may but also may act as aalso membrane-bound act as a moleculemembrane by‐ formingbound amolecule heterotrimeric by formingcomplex a with heterotrimeric LTβ (predominantly complex with LTα1 LTβ2,β but(predominantly also LTα2β1) [LT1,2α].1β Transmembrane2, but also LTα LT2βαβ1) [1,2].heterotrimer Transmembrane and LIGHT LTαβ signalheterotrimer via distinct and LT LIGHTβRs (lymphotoxin signal via distinct beta-receptors), LTβRs (lympho whereas‐ toxintmTNF beta predominantly‐receptors), whereas interacts tmTNF with predominantly p75 TNFR2. The interacts primary with role p75 of TNFR2. TNF is The immune pri‐ maryregulation. role of TNFTNF viais immune its receptors regulation. activates TNF multiple via its signalingreceptors cascades activates leading multiple to signaling induction cascadesof inflammation, leading to cell induction death, or of cell inflammation, survival and iscell implicated death, or bothcell survival in cancer and development is impli‐ catedand progression.both in cancer LT developmentαβ–LTβR signaling and progression. is the key LT pathwayαβ–LTβR in signaling the formation is the key of lymph path‐ waynodes in andthe formation Peyer’s patches of lymph (PP), nodes although and itPeyer’s is not clearpatches whether (PP), although TNF may it be is absolutely not clear whetherrequired TNF for themay development be absolutely of required normal for PP, the since development different TNF of normal knockout PP, strains since differ either‐ entdevelop TNF knockout or lack PP strains [3–6]. either Lymphotoxin develop or has lack specific PP [3–6]. roles Lymphotoxin in the secondary has specific lymphoid roles tis- insue’s the secondary organogenesis lymphoid and in tissue’s supporting organogenesis lymphoid and microenvironments, in supporting lymphoid but also microen in host‐ vironments,defense and but inflammation. also in host Thus,defense TNF and and inflammation. LTα are indispensable Thus, TNF for and maintaining LTα are indispen immune‐ sablesystem for developmentmaintaining immune and homeostasis; system development at the same and time, homeostasis; these cytokines at the have same distinct time, thesenon-overlapping cytokines have roles distinct in inflammation. non‐overlapping roles in inflammation. FigureFigure 1. 1. LigandsLigands and and receptors receptors of of the the tumor tumor necrosis necrosis factor factor (TNF)/lymphotoxin (TNF)/lymphotoxin (LT) (LT) axis. axis. Tumor Tumor necrosisnecrosis factor factor (TNF) (TNF) exists exists in in either either soluble soluble (sTNF) (sTNF) or trans trans-membrane‐membrane (tmTNF) formform andand inte-ractsinte‐ ractswith with its two its two receptors: receptors: TNFR1 TNFR1 (TNFp55) (TNFp55) and and TNFR2 TNFR2 (TNFp75). (TNFp75). Another Another ligand ligand for for TNF TNF receptors re‐ ceptors(TNFRs) (TNFRs) is lymphotoxin is lymphotoxinα homotrimer α homotrimer (LTα3) (LT that,α3) in that, addition, in addition, binds herpesbinds herpes virus entry virus mediatorentry mediator(HVEM). (HVEM). HVEM, lymphotoxinHVEM, lymphotoxinβ receptor β receptor (LTβR), (LT andβR), decoy and receptordecoy receptor 3 (DcR3) 3 (DcR3) are receptors are re‐ for ceptorsLIGHT, for while LIGHT, LTβ Rwhile also interactsLTβR also with interacts LTαβ heterotrimer,with LTαβ heterotrimer, a membrane-bound a membrane form‐bound of lymphotoxin. form of lymphotoxin. The history of TNF is closely related to the history of cancer immunotherapy. William ColeyThe was history the firstof TNF to use is closely endotoxin-induced related to the history antitumor of cancer activity immunotherapy. to treat inoperable William sar- Coleycomas was [7]. the In first the late to use 1960s, endotoxin a cytotoxic‐induced factor, antitumor produced activity by lymphocytes to treat inoperable in response sarco to‐ mastheir [7]. interaction In the late with 1960s, specific a cytotoxic antigens factor, [8 ],produced or as a result by lymphocytes of mitogenic in response stimulation, to their was interactiondescribed with [9] and specific named antigens lymphotoxin [8], or as [10 a result]. However, of mitogenic one cannot stimulation, exclude was that described this cyto- [9]toxic and substance named lymphotoxin contained not [10].