The unexpected role of lymphotoxin beta receptor signaling in carcinogenesis: from lymphoid tissue formation to liver and prostate cancer development

The cytokines lymphotoxin (LT) alpha, beta and their receptor (LT beta R) belong to the tumor necrosis factor (TNF) superfamily, whose founder-TNF alpha-was initially discovered due to its tumor necrotizing activity. LT beta R 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 LTbR comprises the noncanonical/canonical nuclear factor-kappa B (NF-kappa B) pathways thus inducing chemokine, cytokine or adhesion molecule expression, cell proliferation and cell survival. Blocking LT beta R signaling or Fc gamma-receptor mediated immunoablation of LT-expressing cells was demonstrated to be beneficial in various infectious or noninfectious inflammatory or autoimmune disorders. Only recently, LT beta R 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, LT beta R 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. Oncogene (2010) 29, 5006-5018; doi:10.1038/onc.2010.260; published online 5 July 2010