Roles of VEGF-Flt-1 signaling in malignant behaviors of oral squamous cell carcinoma

• Published in: PloS one Vol. 12; no. 11; p. e0187092
• Main Authors: Subarnbhesaj, Ajiravudh, Miyauchi, Mutsumi, Chanbora, Chea, Mikuriya, Aki, Nguyen, Phuong Thao, Furusho, Hisako, Ayuningtyas, Nurina Febriyanti, Fujita, Minoru, Toratani, Shigeaki, Takechi, Masaaki, Niida, Shumpei, Takata, Takashi
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 17.11.2017; Public Library of Science (PLoS)
• Subjects: AKT protein; Angiogenesis; Biocompatibility; Biology and Life Sciences; Biomedical materials; Bone marrow; Cancer therapies; Cell activation; Cell culture; Cell migration; Development and progression; Differentiation; Endothelial cells; Enzyme inhibitors; Extracellular signal-regulated kinase; Genetic aspects; Head & neck cancer; Health sciences; Inhibitors; Kinases; Maxillofacial surgery; Medical prognosis; Medicine and Health Sciences; Metastasis; Oral cancer; Oral squamous cell carcinoma; Osteoclastogenesis; Osteoclasts; Patients; Phosphorylation; Physiological aspects; Physiology; Polyclonal antibodies; Protein-tyrosine kinase; Rodents; Signal transduction; Signaling; Squamous cell carcinoma; TRANCE protein; Tumor cells; Tyrosine; Vascular endothelial growth factor; Japan
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0187092

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. We aimed to clarify the detailed roles of VEGF-Flt-1 signaling in bone invasion of oral squamous cell carcinoma (OSCC) cells. Forty-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). VEGF-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.