Head and neck squamous cell carcinoma (HNSCC) poses a significant challenge clinically where one of the mechanisms responsible for the invasion into facial bones occurs via the activation of osteoclasts. Copper has been demonstrated to play a key role in skeletal remodeling. However, the role of copper in cancer-associated bone destruction is thus far unknown. Lysyl oxidase (LOX) is a copper-dependent enzyme that promotes osteoclastogenesis. In the present study, we investigated the effects of copper on HNSCC with bone invasion by the copper chelator, ammonium tetrathiomolybdate (TM) in vitro and in vivo. We demonstrate that TM blocks the proliferation of HNSCC cells, inhibits LOX activation and decreases the expression of the receptor activator of nuclear factor-κB ligand (RANKL) in osteoblasts and osteocytes, subsequently suppressing bone destruction. These findings suggest that copper is a potential target for the treatment of HNSCCs associated with bone destruction.

Head and neck squamous cell carcinomas (HNSCCs) frequently invade the bones of the facial skeleton. Semaphorin 4D (Sema4D) is an axon guidance molecule produced by oligodendrocytes. Sema4D was also identified in the bone microenvironment and many cancer tissues including HNSCC. To date, however, the role of Sema4D in cancer-associated bone disease is still unknown. This is the first study to demonstrate the role of Sema4D in bone invasion of cancer. In the clinical tissue samples of bone lesion of HNSCC, Sema4D was detected at high levels, and its expression was correlated with insulin-like growth factor-I (IGF-I) expression. In vitro experiments showed that IGF-I regulates Sema4D expression and Sema4D increased proliferation, migration and invasion in HNSCC cells. Sema4D also regulated the expression of receptor activator of nuclear factor κβ ligand (RANKL) in osteoblasts, and this stimulated osteoclastgenesis. Furthermore, knockdown of Sema4D in HNSCC cells inhibited tumor growth and decreased the number of osteoclasts in a mouse xenograft model. Taken together, IGF-I-driven production of Sema4D in HNSCCs promotes osteoclastogenesis and bone invasion.

Background: According to the report of Japan's Ministry of Health, Labor and Welfare, looking at the main reasons requiring nursing care by age group, elderly people aged 75 and over, falls and fractures increase. The purpose of this study was to investigate the trends and characteristic features of maxillofacial fractures in over 75 years old, late stage of elderly patients.Patients and Methods: Records of patients who were treated for maxillofacial fractures at the Oral and Maxillofacial Surgery department (Biopathology) of Okayama University hospital from January 2008 to December 2013 were retrospectively analyzed. Clinical records were analyzed in terms of age, gender, etiology, relevant medical history, and anatomical site of fracture. Patients (n=103) were divided into two groups by age: <75 years and elderly (75 years and older).Results: Falls were responsible for the majority of fractures in the elderly group (81%). The condylar process was the most common fracture site (53.8%), among which cases 85.7% were accompanied with dislocation. The depth of the mandibular fossa was significantly shallower in the elderly than in young (age 10-29 years) patients. Conclusion:In planning treatment, it is important to understand the characteristics and disease state of maxillofacial fractures of the elderly.