Oncogene (2010) 29, 5006–5018 & 2010 Macmillan Publishers Limited All rights reserved 0950-9232/10 www.nature.com/onc REVIEW The unexpected role of lymphotoxin b receptor signaling in carcinogenesis: from lymphoid tissue formation to liver and prostate cancer development MJ Wolf1, GM Seleznik1, N Zeller1,3 and M Heikenwalder1,2 1Department of Pathology, Institute of Neuropathology, University Hospital Zurich, Zurich, Switzerland and 2Institute of Virology, Technische Universita¨tMu¨nchen/Helmholtz Zentrum Mu¨nchen, Munich, Germany The cytokines lymphotoxin (LT) a, b and their receptor genesis. Consequently, the inflammatory microenviron- (LTbR) belong to the tumor necrosis factor (TNF) super- ment was added as the seventh hallmark of cancer family, whose founder—TNFa—was initially discovered (Hanahan and Weinberg, 2000; Colotta et al., 2009). due to its tumor necrotizing activity. LTbR signaling This was ultimately the result of more than 100 years of serves pleiotropic functions including the control of research—indeed—the first observation that tumors lymphoid organ development, support of efficient immune often arise at sites of inflammation was initially reported responses against pathogens due to maintenance of intact in the nineteenth century by Virchow (Balkwill and lymphoid structures, induction of tertiary lymphoid organs, Mantovani, 2001). Today, understanding the underlying liver regeneration or control of lipid homeostasis. Signal- mechanisms of why immune cells can be pro- or anti- ing through LTbR comprises the noncanonical/canonical carcinogenic in different types of tumors and which nuclear factor-jB (NF-jB) pathways thus inducing cellular and molecular inflammatory mediators (for chemokine, cytokine or adhesion molecule expression, cell example, macrophages, lymphocytes, chemokines or proliferation and cell survival. Blocking LTbR signaling or cytokines) drive or potentially prevent carcinogenesis Fcc-receptor mediated immunoablation of LT-expressing is subject of intense research (Supplementary material). cells was demonstrated to be beneficial in various infectious Here, we focus on the cytokines lymphotoxin (LT) a or noninfectious inflammatory or autoimmune disorders. and b and their involvement in inflammation-induced Only recently, LTbR signaling was shown to initiate carcinogenesis. inflammation-induced carcinogenesis, to influence primary tumorigenesis and to control reemergence of carcinoma in various cancer models through distinct mechanisms. Indeed, LTbR signaling inhibition has already been used LT, a molecule with a long history as efficient anti-inflammatory, anti-cancer therapy in some experimental models. Here, we review the pleiotropic In the 1960s and early 1970s, two molecules were functions attributed to LT, the effects of its deregulation described based on their ability to promote cell death and extensively discuss the recent literature on LT’s in target cells (for example, L cells; fibroblasts) (Ruddle link to carcinogenesis. and Waksman, 1967; Granger and Williams, 1968). Oncogene (2010) 29, 5006–5018; doi:10.1038/onc.2010.260; In 1967, a ‘cytotoxic factor’ was described causing published online 5 July 2010 toxicity on fibroblasts in presence of specific antigens (Ruddle and Waksman, 1967, 1968). Further, in 1968, Keywords: lymphotoxin b receptor signaling; inflamma- a cytotoxic molecule produced by lymphocytes was tion-induced carcinogenesis; NF-kB signaling; lympho- reported and named LT (Granger and Williams, 1968; toxin a; lymphotoxin b Granger et al., 1969). In 1975, a substance was depicted causing efficient necrosis in various tumor types in vivo throughout a cytotoxic activity and was thus denomi- nated ‘tumor necrosis factor’ (TNF) (Carswell et al., Inflammation-induced carcinogenesis 1975). These molecules subsequently caught attention of several research groups using these cytotoxic, tumor- In the last decade, several studies have corroborated the necrotizing capabilities for their therapeutic potential in tight link between chronic inflammation and carcino- the treatment of human cancer. In 1984, human LT was the first cytokine to be purified from a b-lymphoblastoid cell line (Aggarwal et al., 1984) and thereafter its amino- Correspondence: Dr M Heikenwalder, Department of Pathology, Institute of Neuropathology, University Hospital Zurich, Schmelz- acid sequence and structure were determined (Aggarwal bergstrasse 12, CH-8091 Zurich, Switzerland. et al., 1985a; Nedwin et al., 1985a). Neutralization of E-mail: [email protected] or LT activity by LT-specific antibodies led to the isolation [email protected] of a second cytotoxic factor from a human myeloid cell 3Current address: Department of Neuropathology, University of Freiburg, D-79106 Freiburg, Germany. line, already known as TNFa (Aggarwal et al., 1985b). Received 1 March 2010; revised 21 May 2010; accepted 27 May 2010; Amino-acid sequence determination revealed close published online 5 July 2010 relationship of TNF to LT, resulting in the renaming Unexpected role of LTbR signaling in carcinogenesis MJ Wolf et al 5007 of LT into TNFb. It became evident that these two cellular stress responses, development and maintenance cytokines are prototypic members of a gene super- of lymphoid organs (Figure 1). family, later defined as the TNF superfamily (TNFSF) Activation of the canonical NF-kB pathway mainly (Hehlgans and Pfeffer, 2005). Interestingly, murine and occurs in response to inflammatory cytokines such as human TNFa and b genes are close to each other within TNF, and IL-1, engagement of the T-cell receptor and in the major histocompatibility complex region (mouse, response to bacterial infection (for example, lipopoly- chromosome 17 (Nedospasov et al., 1986a, b); man, saccharide). Interestingly, LTbR activation (through short arm of chromosome 6 (Nedwin et al., 1985b; LIGHT or LTab heterotrimers) can also activate the Muller et al., 1987)). Later a third ligand—homologous canonical NF-kB (Dejardin et al., 2002; Muller and to TNFb—was identified within the major histocompa- Siebenlist, 2003; Haybaeck et al., 2009). tibility complex locus and named LTb (TNFSF3; In addition to the canonical pathway a parallel (Hiserodt et al., 1977; Ware and Granger, 1979; signaling cascade exists called noncanonical pathway Browning et al., 1993; Pokholok et al., 1995), whereas of NF-kB activation. Stimulation of a subset of TNFR subsequently TNFb was termed LTa or TNFSF1B. At family members, such as LTbR and CD40, can activate present, 19 different ligands belong to the TNFSF, the noncanonical NF-kB pathway (Coope et al., 2002; including, for example, TRAIL, RANKL, BAFF, CD40 Pomerantz and Baltimore, 2002). These stimuli appear (Aggarwal, 2003), mediating their cellular response to converge upon NF-kB-inducing kinase (Xiao et al., through 29 receptors, which contain an extracellular 2001), which is required for IKKa phosphorylation cysteine-rich domain (Aggarwal, 2003) and in some (Ling et al., 1998). In this pathway, IKKa is thought to cases (for example, TNFR1, TNFR2, TRAIL R1, exist as a homodimer, independent of NEMO/IKKg TRAIL R2, Fas) a death domain. and IKKb (Senftleben et al., 2001). Activated IKKa phosphorylates p100, thereby inducing its proteasome- dependent processing to p52. The p52/RelB dimer LT, LTbR and their cellular origin then translocates into the nucleus to induce gene expres- sion through NF-kB activation by the LTa1b2,LTbR, Under physiological conditions, LT is expressed by NF-kB-inducing kinase, IKKa pathway. This pathway T-, B-, natural killer (NK)- and lymphoid tissue-inducer is crucial for development and maintenance of spleen cells (Aggarwal et al., 2003). Although LTa mRNA architecture, follicular dendritic cell maturation, lymph expression is inducible in B-cells, LTb mRNA is node, Peyer’s patch and NALT organogenesis as well as constitutively produced (Browning et al., 1993; Worm regulation of B-cell survival (Weih and Caamano, 2003). and Geha, 1994). LTb is exclusively anchored in Studies with mutant mice showed a phenotypic overlap the membrane as a type II transmembrane protein, between LT or LTbR deficiencies and inactivated NF- binding LTa to form membrane-anchored heterotrimers kB signaling (Bonizzi and Karin, 2004; Bonizzi et al., (LTa1b2 and LTa2b1; Browning et al., 1993, 1995). 2004). Some of these findings are currently challenged LTab heterotrimers can also be cleaved from the cell by recently published results in vitro (Britanova et al., surface by matrix metalloproteases eliciting responses 2008). Thus, explanations for the noncanonical pathway on distal cells (Young et al., 2010). In contrast to LTb, specificity await further experiments. À/À À/À À/À LTa can be secreted as a soluble LTa3 homotrimer. LTa ,LTb and LTbR mice display severe LTa and TNF homotrimers bind and signal through the developmental defects in lymph node and Peyer’s TNF receptors TNFR1 or TNFR2. LTa1b2 triggers patch neogenesis, a disorganized lymphoid micro- LTbR, whereas LTa2b1 was reported to bind TNFR1 architecture and lack of mature follicular dendritic cells and TNFR2, but this is a diminutive LT form expressed (Pfeffer et al., 1993; De Togni et al., 1994; Koni et al., by T-cells (o2%) with an undefined biological role 1997; Futterer et al., 1998; Ngo et al., 1999). In addition, (Ware, 2005). LIGHT (TNFSF14) is an alternative LTaÀ/À and LTbRÀ/À mice show inflammatory disorders ligand for the LTbR but also interacts with herpesvirus in nonlymphoid organs (for example, lung, liver, kidney; entry mediator (Schneider