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 (LTbetaR) belong to the tumor necrosis factor (TNF) superfamily, whose founder-TNFalpha-was initially discovered due to its tumor necrotizing activity. LTbetaR 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 LTbetaR comprises the noncanonical/canonical nuclear factor-kappaB (NF-kappaB) pathways thus inducing chemokine, cytokine or adhesion molecule expression, cell proliferation and cell survival. Blocking LTbetaR signaling or Fcgamma-receptor mediated immunoablation of LT-expressing cells was demonstrated to be beneficial in various infectious or noninfectious inflammatory or autoimmune disorders. Only recently, LTbetaR 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, LTbetaR 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.
Wolf
M J
MJ
Department of Pathology, Institute of Neuropathology, University Hospital Zurich, Zurich, Switzerland.
Seleznik
G M
GM
Zeller
N
N
Heikenwalder
M
M
D000818:Animals; D002277:Carcinoma / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D006801:Humans; D008113:Liver Neoplasms / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D008221:Lymphoid Tissue / Q000502:physiology*; D053259:Lymphotoxin beta Receptor / Q000235:genetics / Q000502:physiology*; D008297:Male; D008954:Models, Biological; D011471:Prostatic Neoplasms / Q000209:etiology* / Q000235:genetics / Q000473:pathology
C505697:LTBR protein, human; D053259:Lymphotoxin beta Receptor