Interleukin-6 signalling regulates vascular endothelial growth factor-C synthesis and lymphangiogenesis in human oral squamous cell carcinoma

Lymph node metastasis is associated with resistance to conventional therapy and poor survival of patients with oral squamous cell carcinoma (OSCC). Although lymphangiogenesis is well known to be associated with the occurrence of lymph node metastasis in various cancers, the precise mechanisms of lym...

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Veröffentlicht in:The Journal of pathology 2011-09, Vol.225 (1), p.142-150
Hauptverfasser: Shinriki, Satoru, Jono, Hirofumi, Ueda, Mitsuharu, Ota, Kazutoshi, Ota, Tomoko, Sueyoshi, Takanao, Oike, Yuichi, Ibusuki, Mutsuko, Hiraki, Akimitsu, Nakayama, Hideki, Shinohara, Masanori, Ando, Yukio
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container_end_page 150
container_issue 1
container_start_page 142
container_title The Journal of pathology
container_volume 225
creator Shinriki, Satoru
Jono, Hirofumi
Ueda, Mitsuharu
Ota, Kazutoshi
Ota, Tomoko
Sueyoshi, Takanao
Oike, Yuichi
Ibusuki, Mutsuko
Hiraki, Akimitsu
Nakayama, Hideki
Shinohara, Masanori
Ando, Yukio
description Lymph node metastasis is associated with resistance to conventional therapy and poor survival of patients with oral squamous cell carcinoma (OSCC). Although lymphangiogenesis is well known to be associated with the occurrence of lymph node metastasis in various cancers, the precise mechanisms of lymphangiogenesis in OSCC are largely unknown. IL‐6, a potent pro‐inflammatory cytokine, has been shown to play active roles in various cancers, including OSCC. This study aimed to investigate the involvement of IL‐6 signalling in lymphatic metastasis and to evaluate the efficacy of tocilizumab, a humanized anti‐human IL‐6 receptor antibody, as an anti‐lymphangiogenic agent for OSCC. This investigation confirmed that levels of expression of IL‐6 protein and VEGF‐C mRNA in OSCC tissues were significantly correlated with lymph node metastasis in patients with OSCC, as assessed by immunohistochemical analysis and real‐time quantitative RT–PCR. In vitro studies showed that IL‐6 regulated VEGF‐C mRNA expression in a human OSCC cell line, SAS cells, through the phosphoinositide 3‐kinase‐Akt pathway. In addition, treatment with tocilizumab led to markedly reduced VEGF‐C mRNA expression and OSCC‐related lymphangiogenesis in SAS xenografts. Together, these data suggest that tocilizumab acted as expected: it inhibited lymph node metastasis in OSCC by reducing tumour lymphangiogenesis. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
doi_str_mv 10.1002/path.2935
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Although lymphangiogenesis is well known to be associated with the occurrence of lymph node metastasis in various cancers, the precise mechanisms of lymphangiogenesis in OSCC are largely unknown. IL‐6, a potent pro‐inflammatory cytokine, has been shown to play active roles in various cancers, including OSCC. This study aimed to investigate the involvement of IL‐6 signalling in lymphatic metastasis and to evaluate the efficacy of tocilizumab, a humanized anti‐human IL‐6 receptor antibody, as an anti‐lymphangiogenic agent for OSCC. This investigation confirmed that levels of expression of IL‐6 protein and VEGF‐C mRNA in OSCC tissues were significantly correlated with lymph node metastasis in patients with OSCC, as assessed by immunohistochemical analysis and real‐time quantitative RT–PCR. In vitro studies showed that IL‐6 regulated VEGF‐C mRNA expression in a human OSCC cell line, SAS cells, through the phosphoinositide 3‐kinase‐Akt pathway. In addition, treatment with tocilizumab led to markedly reduced VEGF‐C mRNA expression and OSCC‐related lymphangiogenesis in SAS xenografts. Together, these data suggest that tocilizumab acted as expected: it inhibited lymph node metastasis in OSCC by reducing tumour lymphangiogenesis. Copyright © 2011 Pathological Society of Great Britain and Ireland. 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Miscellaneous investigative techniques ; Phosphatidylinositol 3-Kinases - physiology ; phosphoinositides ; Phosphorylation - drug effects ; Polymerase chain reaction ; Proto-Oncogene Proteins c-akt - physiology ; RNA, Messenger - genetics ; RNA, Neoplasm - genetics ; Signal transduction ; Signal Transduction - physiology ; tocilizumab ; Tumor Cells, Cultured ; Tumors ; Upper respiratory tract, upper alimentary tract, paranasal sinuses, salivary glands: diseases, semeiology ; Vascular Endothelial Growth Factor C - biosynthesis ; Vascular Endothelial Growth Factor C - genetics ; vascular endothelial growth factor-C ; Xenograft Model Antitumor Assays ; Xenografts</subject><ispartof>The Journal of pathology, 2011-09, Vol.225 (1), p.142-150</ispartof><rights>Copyright © 2011 Pathological Society of Great Britain and Ireland. 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This investigation confirmed that levels of expression of IL‐6 protein and VEGF‐C mRNA in OSCC tissues were significantly correlated with lymph node metastasis in patients with OSCC, as assessed by immunohistochemical analysis and real‐time quantitative RT–PCR. In vitro studies showed that IL‐6 regulated VEGF‐C mRNA expression in a human OSCC cell line, SAS cells, through the phosphoinositide 3‐kinase‐Akt pathway. In addition, treatment with tocilizumab led to markedly reduced VEGF‐C mRNA expression and OSCC‐related lymphangiogenesis in SAS xenografts. Together, these data suggest that tocilizumab acted as expected: it inhibited lymph node metastasis in OSCC by reducing tumour lymphangiogenesis. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley &amp; Sons, Ltd.</abstract><cop>Chichester, UK</cop><pub>John Wiley &amp; Sons, Ltd</pub><pmid>21710490</pmid><doi>10.1002/path.2935</doi><tpages>9</tpages></addata></record>
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subjects Aged
Animals
Antibodies
Antibodies, Monoclonal - pharmacology
Antibodies, Monoclonal - therapeutic use
Antibodies, Monoclonal, Humanized
Antineoplastic Agents - pharmacology
Antineoplastic Agents - therapeutic use
Biological and medical sciences
Carcinoma, Squamous Cell - drug therapy
Carcinoma, Squamous Cell - genetics
Carcinoma, Squamous Cell - physiopathology
Carcinoma, Squamous Cell - secondary
Cell survival
Data processing
Drug Evaluation, Preclinical - methods
Female
Gene expression
Gene Expression Regulation, Neoplastic - drug effects
Hematologic and hematopoietic diseases
Humans
Inflammation
Interleukin 6
Interleukin 6 receptors
Interleukin-6 - physiology
interleukin-6 receptor
Investigative techniques, diagnostic techniques (general aspects)
Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis
lymph node metastasis
Lymph nodes
lymphangiogenesis
Lymphangiogenesis - drug effects
Lymphangiogenesis - physiology
Male
Medical sciences
Metastases
Mice
Mice, SCID
Middle Aged
Mouth Neoplasms - drug therapy
Mouth Neoplasms - genetics
Mouth Neoplasms - physiopathology
oral squamous cell carcinoma
Otorhinolaryngology. Stomatology
Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques
Phosphatidylinositol 3-Kinases - physiology
phosphoinositides
Phosphorylation - drug effects
Polymerase chain reaction
Proto-Oncogene Proteins c-akt - physiology
RNA, Messenger - genetics
RNA, Neoplasm - genetics
Signal transduction
Signal Transduction - physiology
tocilizumab
Tumor Cells, Cultured
Tumors
Upper respiratory tract, upper alimentary tract, paranasal sinuses, salivary glands: diseases, semeiology
Vascular Endothelial Growth Factor C - biosynthesis
Vascular Endothelial Growth Factor C - genetics
vascular endothelial growth factor-C
Xenograft Model Antitumor Assays
Xenografts
title Interleukin-6 signalling regulates vascular endothelial growth factor-C synthesis and lymphangiogenesis in human oral squamous cell carcinoma
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