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Roles of VEGF-Flt-1 signaling in malignant behaviors of oral squamous cell carcinoma
BACKGROUND: 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...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5693288/ https://www.ncbi.nlm.nih.gov/pubmed/29149180 http://dx.doi.org/10.1371/journal.pone.0187092 |
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author | 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 |
author_facet | 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 |
author_sort | Subarnbhesaj, Ajiravudh |
collection | PubMed |
description | BACKGROUND: 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. OBJECTIVES: We aimed to clarify the detailed roles of VEGF-Flt-1 signaling in bone invasion of oral squamous cell carcinoma (OSCC) cells. RESULTS: 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). CONCLUSION: 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. |
format | Online Article Text |
id | pubmed-5693288 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-56932882017-11-30 Roles of VEGF-Flt-1 signaling in malignant behaviors of oral squamous cell carcinoma 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 PLoS One Research Article BACKGROUND: 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. OBJECTIVES: We aimed to clarify the detailed roles of VEGF-Flt-1 signaling in bone invasion of oral squamous cell carcinoma (OSCC) cells. RESULTS: 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). CONCLUSION: 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. Public Library of Science 2017-11-17 /pmc/articles/PMC5693288/ /pubmed/29149180 http://dx.doi.org/10.1371/journal.pone.0187092 Text en © 2017 Subarnbhesaj et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article 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 Roles of VEGF-Flt-1 signaling in malignant behaviors of oral squamous cell carcinoma |
title | Roles of VEGF-Flt-1 signaling in malignant behaviors of oral squamous cell carcinoma |
title_full | Roles of VEGF-Flt-1 signaling in malignant behaviors of oral squamous cell carcinoma |
title_fullStr | Roles of VEGF-Flt-1 signaling in malignant behaviors of oral squamous cell carcinoma |
title_full_unstemmed | Roles of VEGF-Flt-1 signaling in malignant behaviors of oral squamous cell carcinoma |
title_short | Roles of VEGF-Flt-1 signaling in malignant behaviors of oral squamous cell carcinoma |
title_sort | roles of vegf-flt-1 signaling in malignant behaviors of oral squamous cell carcinoma |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5693288/ https://www.ncbi.nlm.nih.gov/pubmed/29149180 http://dx.doi.org/10.1371/journal.pone.0187092 |
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