Signaling through the lymphotoxin beta receptor induces the death of some adenocarcinoma tumor lines.

Abstract

SummarySurface lymphotoxin (LT) is a heteromeric complex of LT-c~ and LT-[3 chains that binds to the LT-I3 receptor (LT-I3-R), a member of the tumor necrosis factor (TNF) family of receptors. The biological function of this receptor-ligand system is poorly characterized. Since signaling through other members of this receptor family can induce cell death, e.g., the TNF and Fas receptors, it is important to determine if similar signaling events can be communicated via the LT-13-tL. A soluble form of the surface complex was produced by coexpression of LT-c~ and a converted form of LT-[3 wherein the normally type II LT-[3 membrane protein was changed to a type I secreted form. Recombinant LT-oq/[32 was cytotoxic to the human adenocarcinoma cell lines HT-29, WiDr, MDA-MB-468, and HT-3 when added with the synergizing agent interferon (IFN) y. When immobilized on a plastic surface, anti-LT-[3-tL monoclonal antibodies (mAbs) induced the death of these cells, demonstrating direct signaling via the LT-I3-R. Anti-LT-[3-R mAbs were also identified that inhibited ligand-induced cell death, whereas others were found to potentiate the activity of the ligand when added in solution. The human WiDr adenocarcinoma line forms solid tumors in immunocompromised mice, and treatment with an anti-LT-~-R, antibody combined with human IFN-~/arrested tumor growth. The delineation of a biological signaling event mediated by the LT-I3-R opens a window for further studies on its immunological role, and furthermore, activation of the LT-I3-R may have an application in tumor therapy.T he TNF family ofligands and receptors is a set of regulatory elements in the immune system (t). TNF was discovered as a cytolytic agent circulating in the blood of endotoxin-stimulated animals (2-4). Originally cloned in the expectation that TNF would be a novel antitumor agent, it was later shown that its primary physiologic function lies in initiating the inflammatory cascade underlying the host's immediate defensive response to infection or stress. More complex immunological functions have been described (5,6). Lymphotoxin (LT) 1 e~ (also called TNF-I3) is a similar cytokine secreted by activated lymphocytes (7) and was originally characterized as having the same functions as TNF. Later, activated T and B cells were found to display LT-c~ on their surfaces in an unusual form compIexed with another member of the TNF family called LT-13 in an . A complex with an apparent 1 Abbreviations used in this paper: LT, lymphotoxin; LT-I3-1L, LT-[3 receptor; MTT, 3-(4,5-dimethylthiazol-2-yl) 2,5 diphenyltetrazolium bromide; TUNEL, terminal deoxynucleotidyl transferase UTP nick-end labeling; VCAM, vascular cell adhesion molecule.LT-c~2/I31 stoichiometry is also present, but only in minor amounts on human lymphocytes. The major LT-cq/f3 z form does not bind to the known TNF receptors, referred to here as TNF-R55 and TNF-R.75, but rather interacts with another receptor in the TNF family called the LT-[3 receptor 14).Currently, the function of the LT system is poorly character...

Differential lymphotoxin-? and interferon gamma signaling during mouse liver regeneration induced by chronic and acute injury

“…In some tumor cells, LT␤ signals apoptosis 37,38 or nonapoptotic growth inhibition, 25 and in WI38 fibroblasts, cellular proliferation. 39 In vivo, LT␤/LT␤R signaling is required for the development of secondary lymph organs, including Peyer's patches and lymph nodes 40 -51 and the cellular composition and organization of the spleen 40 -42,48 -51 and lamina propria.…”

Targeting tumors with LIGHT to generate metastasis-clearing immunity

“…For example, apoptosis of cancer cells induced by chemotherapeutic agents or radiation releases antigen, enhancing the cross-priming of T cells [65,66]. LIGHT has been shown to signal via LTβR and/or HVEM expressed on the tumor cells to induce apoptosis of the tumor cells, especially in the presence of interferon-γ [4,5,67]. Using a xenograft tumor model in which human breast cancer cells were inoculated to athymic nude mice, LIGHT directly inhibited tumor growth by causing apoptosis in the absence of T cells [68].…”

Identification of novel growth factor-responsive genes in neuroendocrine gastrointestinal tumour cells

“…Moreover, gastrin was shown to downregulate the expression of lymphotoxin beta receptor (LTBR). Activation of this receptor has been shown to induce apoptosis in some tumour cells (Browning et al, 1996), and thus a downregulation of its expression probably undermines its apoptotic effect.…”