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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2017
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.
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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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