Abstract
Bone invasion represent significant problem in managing head and neck cancers, however the mechanisms of interactions between oral squamous cell carcinoma (OSCC) and bone cells are poorly understood. We hypothesized that tumor cells can directly stimulate osteoclastogenesis.
OSCC cell lines, bone-invasive BHY and metastatic but not bone-invasive HN were cultured and conditioned medium (CM) was collected. Osteoclast formation from RAW 264.7 mouse monocytic cell-line was assessed.
When RAW 264.7 were primed with receptor activator of nuclear factor? B ligand (RANKL) and then treated with BHY-CM, marked 2–6-fold induction of osteoclastogenesis was observed. In contrast, HN-CM did not significantly affect osteoclastogenesis. In addition, BHY-CM, but not HN-CM promoted survival of mature osteoclasts. Using pharmacological inhibitors, we found that Protein kinase C (PKC)/Extracellular signal-regulated kinase (ERK)1/2/Mitogen activated protein kinase (MAPK) p38 as well as Phosphatidyl-inositol 3-kinases (PI3K)/Serine/threonine protein kinase Akt/Mammalian target of rapamycin (mTOR) pathways mediate BHY-CM induced osteoclastogenesis.
Thus, we demonstrated that bone-invasive squamous cell carcinoma cells produce soluble factors that stimulate osteoclast formation from RANKL-primed precursors in the absence of supporting cell types, acting through both physiological osteoclastogenic pathways and tumor-specific signaling. In the future, this study may help to develop prognostic markers for oral squamous cell carcinoma bone invasiveness, as well as new therapeutic treatments specifically targeting tumor-stimulated pathways in osteoclasts.