LIGHT/TNFSF14 Promotes Osteolytic Bone Metastases in Non-small Cell Lung Cancer Patients

Abstract

Tumor necrosis factor superfamily member 14 (TNFSF14), LIGHT, is a component of the cytokine network that regulates innate and adaptive immune responses, which promote homeostasis of lymphoid organs, liver, and bone. Metastatic tumors often disrupt the tissue microenvironment, thus altering the homeostasis of the invaded organ; however, the underlying mechanisms required further studies. We investigated the role of LIGHT in osteolytic bone disease induced by metastatic non‐small cell lung cancer (NSCLC). Patients diagnosed with NSCLC bone metastasis show significantly higher levels of LIGHT expressed in monocytes compared with non‐bone metastatic tumors and healthy controls. Serum LIGHT levels were also higher in patients with bone metastases than in controls, suggesting a role for LIGHT in stimulating osteoclast precursors. In bone metastatic patients, we also detected increased RNA expression and serum RANKL levels, thus by adding anti‐LIGHT or RANK–fragment crystallizable region (RANK‐Fc) in PBMC cultures, a significant inhibition of osteoclastogenesis was observed. To model this observation in mice, we used the mouse lung cancer cell line LLC‐1. After intratibial implantation, wild‐type mice showed an increased number of osteoclasts but reduced numbers of osteoblasts and decreased osteoid formation. In contrast, Tnfsf14−/− mice showed no significant bone loss or other changes in bone homeostasis associated with this model. These data indicate LIGHT is a key control mechanism for regulating bone homeostasis during metastatic invasion. Thus, LIGHT may be a novel therapeutic target in osteolytic bone metastases. © 2019 American Society for Bone and Mineral Research.

BMP2 signalling activation enhances bone metastases of non‐small cell lung cancer

“…Osteoclasts, the only cells capable of bone resorption, derived from myeloid lineage, were reported to be controlled by RANKL, PTHrP and Jagged 1 61‐64 . In a recent report, LIGHT (tumour necrosis factor superfamily member 14, TNFSF14), derived from monocytes, was shown to promote osteolysis in NSCLC bone metastases and could be a new therapy target 65 . RANKL can be secreted by osteoblast lineages or stromal cells, and PTHrp can be derived from tumour cells 61,66‐68 .…”

Shedding “LIGHT” on the Link between Bone and Fat in Obese Children and Adolescents

“…Furthermore, here we also demonstrated LIGHT involvement in the spontaneous osteoclastogenesis, in vitro, in PBMC of obese patients. Consistently, LIGHT is a pro-osteoclastogenic cytokine [ 21 ] and high levels have been demonstrated in erosive bone disease, firstly in rheumatoid arthritis [ 48 ] and then by bone metastatic non-small cell lung cancer (NSCLC), in osteolytic multiple myeloma, alkaptonuria, chronic kidney disease (CKD), hemodialysis patients, and post-menopausal osteoporosis [ 19 , 21 , 22 , 23 , 24 , 25 ]. In these different diseases with bone involvement, the elevated LIGHT levels are primarily correlated to its pro-osteoclastogenic role, as we and other authors have reported [ 21 , 48 ].…”

“…In parallel, many pro-inflammatory cytokines involved in obesity are also crucial mediators of osteoclastogenesis, with consequent increase of bone resorption activity [ 18 ], and thus supporting the link between obesity and altered bone turnover. One of these cytokines could be represented by LIGHT (homologous to Lymphotoxins exhibiting Inducible expression and competing with herpes simplex virus Glycoprotein D for herpes virus entry mediator (HVEM), a receptor expressed by T lymphocytes) [ 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 ]. LIGHT/TNFSF14 is member of TNF superfamily and it is a key cytokine of the TNF-lymphotoxin network [ 27 , 28 , 29 ], expressed by immune cells, with a key role as a co-stimulatory molecule [ 30 ].…”

LIGHT/TNFSF14 regulates estrogen deficiency‐induced bone loss

“…In 2006, Edwards et al first demonstrated in rheumatoid arthritis that LIGHT (a co-stimulatory molecule) is involved in erosive bone disease [8]. We then deepened the understanding of LIGHT's role in bone remodeling in the pathologies of multiple myeloma, lung cancer, CKD, and alkaptonuria [9,[11][12][13]29]. In 2018, we studied the bone phenotype of Tnfsf14 −/− mice and demonstrated trabecular bone loss, suggesting that a physiological basal concentration of LIGHT is required to maintain physiological bone remodeling [10].…”