Abstract
BackgroundVascular endothelial growth factor (VEGF) is a highly specific signaling protein for vascular endothelial cells that plays a critical role in tumor growth and invasion through angiogenesis, and may contribute to cell migration and activation of pre-osteoclasts, osteoclasts and some tumor cells.ObjectivesWe aimed to clarify the detailed roles of VEGF-Flt-1 signaling in bone invasion of oral squamous cell carcinoma (OSCC) cells.ResultsForty-two (42) of 54 cases with gingival SCC (77.8%) strongly expressed VEGF, and had a significantly increased number of Flt-1+ osteoclasts (p<0.01) and more aggressive bone invasion (p<0.05). PlGF, a ligand of Flt-1, induced osteoclastogenesis in single culture of bone marrow cells (BMCs), and inhibition of Flt-1-signaling by VEGF tyrosine kinase inhibitor and It’s down stream (Akt and ERK1/2) inhibitos reduced osteoclastogenesis in PlGF-stimulated BMCs (p<0.01). In molecular level, PlGF stimulation significantly upregulated RANKL expression in Flt-1-expressing HSC2 cells via phosphorylation of Akt and ERK1/2. In the co-culture of VEGF-producing HSC2 cells and BMCs, number of TRAP-positive osteoclasts markedly increased (p<0.01). The osteoclastogenesis was significantly inhibited by RANKL-neutralizing antibody (p<0.01) as well as by VEGF tyrosine kinase inhibitor (p<0.01) and it’s downstream (Akt and ERK1/2) inhibitors (p<0.01, p<0.05, respectively).ConclusionVEGF-Flt-1 signaling induces osteoclastogenesis in OSCC through two possible ways: 1) VEGF produced from OSCC cells can directly stimulate the Flt-1 pathway in preosteoclasts to induce migration to future bone resorbing area and differentiation into osteoclasts, and 2) VEGF-Flt-1 signaling upregulates RANKL expression in OSCC cells, which indirectly leads to osteoclast differentiation. Therefore, blocking of the VEGF-Flt-1 signaling may help inhibit bone invasion of OSCC.
Highlights
Head and neck cancers represent the sixth most common cancer worldwide; approximately 630,000 new patients are diagnosed annually, and there are more than 350,000 deaths every year [1]
Our findings support that Vascular endothelial growth factor (VEGF)-Flt-1 signaling is important in the facilitation of bone destruction and bone invasion of gingival oral squamous cell carcinoma (OSCC)
VEGF and oral squamous cell carcinoma caused by VEGF producing OSCCs; direct pathway and indirect pathway
Summary
Head and neck cancers represent the sixth most common cancer worldwide; approximately 630,000 new patients are diagnosed annually, and there are more than 350,000 deaths every year [1]. More than 90% of head and neck cancers are squamous cell carcinoma (SCC), which mainly occurs in the oral cavity and oropharynx, so-called oral squamous cell carcinoma (OSCC) [3,4]. OSCC has highly malignant behaviors, including invasion, recurrence and metastasis. Gingival SCC, in particular, frequently invades into the underlying bone. This event can lead to a poor prognosis, and the treatments such as mandibulectomy, radiation and chemotherapy can tremendously reduce the quality of life of OSCC patients [6,7]. Vascular endothelial growth factor (VEGF) is a highly specific signaling protein for vascular endothelial cells that plays a critical role in tumor growth and invasion through angiogenesis, and may contribute to cell migration and activation of pre-osteoclasts, osteoclasts and some tumor cells
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