RESUMO
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.
Assuntos
Antineoplásicos Imunológicos/farmacologia , Neoplasias Ósseas/tratamento farmacológico , Reabsorção Óssea/tratamento farmacológico , Carcinoma de Células Escamosas/tratamento farmacológico , Quelantes/farmacologia , Cobre/metabolismo , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Osteoclastos/efeitos dos fármacos , Animais , Antineoplásicos Imunológicos/uso terapêutico , Neoplasias Ósseas/patologia , Neoplasias Ósseas/secundário , Reabsorção Óssea/patologia , Carcinoma de Células Escamosas/patologia , Cetuximab/farmacologia , Cetuximab/uso terapêutico , Quelantes/uso terapêutico , Sinergismo Farmacológico , Feminino , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Nus , Molibdênio/farmacologia , Molibdênio/uso terapêutico , Invasividade Neoplásica/patologia , Osteoclastos/fisiologia , Proteína-Lisina 6-Oxidase/metabolismo , Ligante RANK/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
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 κß 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.
