osteoprotegerin and Mandibular-Neoplasms

To determine the distribution patterns of bone resorption regulators, receptor activator of nuclear factor κ-B (RANK), RANK ligand (RANKL), and osteoprotegerin (OPG) in recurrent ameloblastoma (RAs) and to clarify their impact on the biologic behavior of these neoplasms.. Fifteen paraffin-embedded RA cases were subjected to immunohistochemistry for expression of RANK, RANKL, and OPG.. The RANK-RANKL-OPG triad was heterogeneously detected in RA samples. RANK, essential for osteoclast differentiation, was strongly expressed in tumoral epithelium. Conversely, RANKL, an osteoclast activator, was markedly underexpressed, and protein localization was predominantly stromal. OPG, an osteoclastogenesis inhibitory factor, was detected in neoplastic epithelium more than in stroma, suggesting functional inactivation of RANKL. Most RA (n = 12/15; 80%) exhibited a bimolecular spatial expression pattern, the most common being RANK-positive/OPG-positive (n = 8/15; 53.3%). All three proteins showed no significant correlation with the clinical/histopathologic parameters in RA patients (P > .05).. The RANK(+)/RANKL(low/-)/OPG(+) phenotype observed in RA suggests an altered local bone metabolism characterized by low bone resorptive activity in these recurrent tumors.

Topics: Adolescent; Adult; Aged; Ameloblastoma; Child; Female; Humans; Immunohistochemistry; Male; Mandibular Neoplasms; Middle Aged; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B

Oral squamous cell carcinomas (OSCCs) are malignant tumors that frequently invade the maxilla and mandibular bone. However, the molecular mechanisms underlying bone invasion by OSCC are unclear. Recent studies showed that receptor activator of nuclear factor κB (RANK) was expressed not only in osteoclast precursors but also in tumor cells. Therefore, we examined whether RANK ligand (RANKL)/RANK signaling regulates bone invasion by OSCC cells in vivo and in vitro. We first injected human OSCC B88 cells into the masseter region of nude mice. Mice were treated for 3 weeks with osteoprotegerin (OPG), the decoy receptor for RANKL. Treatment with OPG decreased bone invasion by B88 cells, reduced the number of osteoclasts and increased B88 cell apoptosis. However, OPG did not affect apoptosis and proliferation in B88 cells in vitro, suggesting that the effects of OPG on apoptosis in B88 cells are restricted in a bone environment. RANK was expressed in the B88 cells and in OSCC cells from patients. RANKL induced NF-κB activation and extracellular signal-regulated kinase phosphorylation in B88 cells and enhanced B88 cell migration in a modified chemotaxis chamber equipped with a gelatin-coated filter. OPG inhibited RANKL-induced NF-κB activation, extracellular signal-regulated kinase phosphorylation and cell migration. Our data clearly indicate that RANKL/RANK inhibition suppresses bone invasion by inhibiting osteoclastogenesis and cancer cell migration and by inducing apoptosis of cancer cells via indirect anticancer action in vivo.

Topics: Animals; Apoptosis; Blotting, Western; Bone Neoplasms; Carcinoma, Squamous Cell; Cell Movement; Cell Proliferation; Electrophoretic Mobility Shift Assay; Extracellular Signal-Regulated MAP Kinases; Humans; Male; Mandibular Neoplasms; Mice; Mice, Inbred BALB C; Mice, Nude; Mouth Neoplasms; Neoplasm Invasiveness; NF-kappa B; Osteoclasts; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Signal Transduction; Tumor Cells, Cultured

The mechanism of oral squamous cell carcinoma (SCC) invading jawbone remains controversial. Interactions between receptor activator of NF-kappaB (RANK) and its ligand (RANKL) are required for osteoclastogenesis. The binding of RANK and RANKL induces differentiation of osteoclasts, leading to bony destruction. Osteoprotegerin (OPG), a decoy receptor for RANKL, also binds to RANKL by competing with RANK, and this could protect against osseous destruction.. Immunoexpression of RANKL, RANK, and OPG in 25 cases of human buccal SCCs without bony invasion and 15 cases of gingival SCCs with mandibular bony invasion was investigated. Normal oral mucosa from five individuals without betel-quid chewing or cigarette smoking was used as a control. The scores are designated as percentage of positive staining x intensity of staining for each section.. Strong cytoplasmic staining of RANKL proteins is detected in cancer cells of both buccal and gingival SCCs. The same protein is identified in cytoplasm of osteoclasts for all cases involving bony invasion. Strong cytoplasmic staining of RANKL is confined to basal layer for all normal mucosa. A similar staining pattern is noted for RANK protein in all buccal and gingival SCCs. An absence of staining of RANK protein is noted for all normal tissues. Weak to negative cytoplasmic stained OPG protein is present in all buccal and gingival SCCs, but is absent in all normal tissues.. These findings suggest the potential value of the RANK/RANKL/OPG pathway as biomarkers in human oral SCCs.

Topics: Adult; Aged; Biomarkers, Tumor; Carcinoma, Squamous Cell; Cell Differentiation; Coloring Agents; Cytoplasm; Female; Gingival Neoplasms; Humans; Immunohistochemistry; Male; Mandibular Neoplasms; Middle Aged; Mouth Mucosa; Mouth Neoplasms; Neoplasm Invasiveness; Neoplasm Staging; Osteoclasts; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B