Bone metastases in gastric cancer follow a RANKL-independent mechanism

Abstract

Abstract. Gastric cancer is one of the most common and lethal malignancies worldwide. Bone metastases in gastric cancer are less common than in other solid tumors, but when they occur the prognosis is generally poor. Increased osteoclastogenesis and osteoclast activity are common features in bone metastases caused by different osteotropic cancer. We investigated osteoclastogenesis and its mechanisms in gastric cancer by enrolling 31 newly diagnosed gastric cancer patients and 45 healthy controls. We studied in vitro osteoclastogenesis in the peripheral blood mononuclear cell cultures of patients and controls, showing spontaneous osteoclastogenesis for half of the patients. This osteoclastogenesis was RANKL-and TNF-α-independent. We analyzed primary tumor and bone metastatic tissues of gastric cancer for the expression of genes involved in osteoclastogenesis. The expression of transforming growth factor-β (TGF-β), osteoprotegerin (OPG), IL-7 and dickkopf-1 (DKK-1) was higher in primary tumors than in bone metastases. RANKL was not detectable in primary tumor or in bone metastatic tissue. The serum RANKL level was significantly higher in healthy controls than in patients, and it was not related to osteoclastogenesis, thereby suggesting that RANKL is not involved in the bone metastatic mechanisms in gastric cancer. We hypothesized a role of RANKL in angiogenesis, thus we compared the serum levels of RANKL to those of VEGF, since VEGF is directly related to angiogenesis. Different from RANKL, the VEGF serum levels were higher in gastric patients than in controls, suggesting a block of the angiogenesis inhibition due to RANKL. RANKL and VEGF serum levels were not predictive of overall survival in our cohort of gastric patients.

Infiltrating Mast Cells Correlate with Angiogenesis in Bone Metastases from Gastric Cancer Patients

“…These correlations suggest that, also in bone tissue, the development of metastases is supported through an angiogenic process stimulated by MCs positive to tryptase ( Figure 3 A). In bone tissue, MCs may be recruited and activated through SCF, the ligand of c-Kit receptor and by means of other growth factors such as, VEGF, FGF and TP, secreted by gastric cancer cells ( Figure 3 A) [ 4 , 28 , 29 , 30 , 43 ]. MCs contain several angiogenic factors including tryptase, VEGF, FGF, IL-8 and the above TNF-alpha that are all characterized by pro-angiogenic properties [ 4 , 11 , 32 , 42 , 44 ].…”

The immune system and postmenopausal osteoporosis

“…OCs precursors circulate within the mononuclear fraction of peripheral blood (D'Amelio et al, 2008;D'Amelio et al, 2010;D'Amelio et al, 2008;D'Amelio et al, 2010;D'Amico et al 2013;Roato et al, 2008). This population acts not only as a reservoir for replenishing pre-OC pool in the bone marrow, but also as a potentially abundant source of pre-OCs that can be recruited into bone or joint tissue in response to reparative or pathological signals.…”

“…OCs precursors increases during estrogen deficiency (D'Amelio et al, 2008) and in condition characterized by increased bone turnover as bone metastases (D'Amico et al 2013;Roato et al, 2007) or inflammatory diseases (Oostlander et al, 2012;Roato et al, 2007;Xue et al, 2012).…”

Bone-Immune Cell Crosstalk: Bone Diseases

“…OC precursors increase during estrogen deficiency [ 47 ] and in condition characterized by increased bone turnover as bone metastases [ 50 , 55 ] or inflammatory diseases [ 55 – 57 ].…”