Lymphotoxin's Link to Carcinogenesis: Friend or Foe? From Lymphoid Neogenesis to Hepatocellular Carcinoma and Prostate Cancer

摘要

It was only in the late 1960s that lymphotoxin (LT) was described and denoted as a "cytotoxic factor." Isolated lymph node cells from rats showed cytotoxic effects on syngeneic or allogeneic fibroblasts in the presence of specific antigens [84, 85]. Besides, in vitro stimulation of murine lymphocytes led to secretion of these earlier described cytotoxic factors into the culture medium, capable of killing various cell types (e.g., L cells) [37, 38]. LT was later isolated from stimulated lymphocytes and characterized in various species including mouse, guinea pig, and human [51, 95] and denned as a "lymphokine" being a non-antibody mediator of cellular immunity generated by lymphocyte activation [36]. In 1984, after purification of the proteins to homogeneity, determination of the amino acid sequence and cloning of the cDNA were accomplished [1, 2, 39]. These studies revealed LT's close relationship to TNFalpha, leading to a renaming of LT into TNFbeta. Later, TNFbeta was called LTalpha or TNFSF1B (for TNFSF member 1B), and subsequently LTbeta (TNFSF3) was described. Of note, besides their biochemical similarities LTa, LTbeta, and TNF (TNFSF1A) are found in close proximity on genomic level, within the major histocompatibility complex region on mouse chromosome 17 (humans: chromosome 6) [71].