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2004 Fiscal Year Final Research Report Summary

Molecular mechanisms of micrometastasis of oral cancer and inhibition of metastasis by molecular target therapy

Research Project

Project/Area Number 14207091
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section一般
Research Field Surgical dentistry
Research InstitutionEhime University

Principal Investigator

HAMAKAWA Hiroyuki  Ehime University, School of Medicine, Professor, 医学部, 教授 (20127905)

Co-Investigator(Kenkyū-buntansha) SHINTANI Satoru  Ehime University, School of Medicine, Associate Professor, 医学部, 助教授 (80294429)
NAKASHIRO Koichi  Ehime University, Hospital, lecturer, 医学部附属病院, 講師 (90314880)
Project Period (FY) 2002 – 2004
KeywordsOral cancer / Metastasis / Molecular target therapy / EGFR / CXCR4 / VEGF / HIF-1 / c-Met
Research Abstract

In this study, we have attempted to clarify molecular mechanisms of micrometastasis of oral cancer in order to block metastasis targeting molecules related to micrometastasis. At first, we established two human oral squamous cell carcinoma (OSCC) cell lines and two human salivary gland cancer cell lines, which stably express green fluorescent protein (GFP) and have different potential of metastasis. Measurements of GFP strength make it possible to evaluate the in vitro invasiveness and in vivo lymph node micrometastasis and distant metastasis of tumor correctly and easily. Some molecules such as vascular endothelial growth factor (VEGF), chemokine receptor CXCR4, epithelial growth factor receptor (EGFR), matrix metalloproteinases (MMPs) and cytokine IL-8 were identified as candidate genes related to metastasis of OSCC by gene expression profile of human OSCC cell lines and OSCC tissues using human genome wide microarray. Further investigation of CXCR4,VEGF, EGFR and IL-8 revealed that … More CXCR4 and EGFR regulated the invasiveness and migration of OSCC cells respectively and VEGF regulated angiogenesis of OSCC tumor. In in vivo tumor model using athymic nude mice orthotopically inoculated with OSCC cells, the blockade of function of CXCR4 or EGFR and the inhibitors of angiogenesis markedly suppressed lymph node metastasis of tumor. Moreover, combination of radiotherapy enhanced their inhibitory effects. On the other hand, investigation of the mechanisms of metastasis in human salivary gland cancer cells suggested that hypoxia-inducible factor-1 (HIF-1) correlated with metastasis of human salivary gland cancer. Under hypoxic condition HIF-1 expression increased in human salivary gland cancer cells which have metastatic potential and hepatocyte growth factor (HGF) receptor/c-Met expression also increased. But in those which have no metastatic potential HIF-1 and c-Met did not increase under hypoxic condition. In addition to these results, many other novel genes related to metastasis of oral cancer were identified by this study. Less

  • Research Products

    (34 results)

All 2004 2003 2002

All Journal Article (34 results)

  • [Journal Article] Expression of vascular endothelial growth factor A,B,C, and D in oral squamous cell carcinoma2004

    • Author(s)
      S Shintani, C Li, M Mihara, T Isikawa, M Mihara, K Nakashiro, H Hamakawa
    • Journal Title

      Oral Oncol 40 (1)

      Pages: 13-20

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Gefinitib ('Iressa', ZD1839), an eppidermal growth factor receptor tyrosine kinase inhibitor, up-regulates p27KIP1 and induces G1 arrest in oral squamous cell carcinoma cell lines2004

    • Author(s)
      S Shintani, C Li, M Mihara, J Yano, N Terakado, K Nakashiro, H Hamakawa
    • Journal Title

      Oral Oncol 40 (1)

      Pages: 43-51

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Basic and clinical studies on quantitative analysis of lymph node micrometastasis in oral cancer2004

    • Author(s)
      A Onishi, K Nakashiro, M Mihara, T Sumida, H Kawamata, S Shintani, T Aida, T Tachikawa, H Hamakawa
    • Journal Title

      Oncol Rep 11 (1)

      Pages: 33-39

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Overexpression of cyclooxygenase-2 is associated with radioresistance in oral squamous cell carcinoma2004

    • Author(s)
      N Terakado, S Shintani, J Yano, C Li, M Mihara, K Nakashiro, Hamakawa H
    • Journal Title

      Oral Oncol 40 (4)

      Pages: 383-389

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Growth regulated oncogene 1 expression is associated with angiogenesis and lymph node metastasis in human oral cancer2004

    • Author(s)
      Shintani S, T.Ishikawa, T.Nonaka, C.Li, K.Nakashiro, D.T.W.Wong, H.Hamakawa
    • Journal Title

      Oral Oncol 66 (4)

      Pages: 316-322

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Skp2 and Jab1 expression are associated with inverse expression of p27KIP1 and poor prognosis in oral squamous cell carcinomas2004

    • Author(s)
      S Shintani, C Li, M Mihara, S Hino, K Nakashiro, H Hamakawa
    • Journal Title

      Oncol 65 (4)

      Pages: 355-362

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Intraoperative real-time genetic diagnosis for sentinel node navigation surgery2004

    • Author(s)
      H Hamakawa, A Onishi, T Sumida, N Terakado, S Hino, K Nakashiro, S Shintani
    • Journal Title

      Int J Oral Max-fac Surg 33 (7)

      Pages: 670-675

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Constitutive activation of Stat3 correlates with increased expression of the c-Met/HGF receptor in oral squamous cell carcinoma2004

    • Author(s)
      Klosek SK, Nakashiro K, Hara S, Li C, Shintani S, Hamakawa H:
    • Journal Title

      Oncol Rep 12 (2)

      Pages: 293-296

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Expression of vascular endothelial growth factor-A, B, C, and D in oral squamous cell carcinoma.2004

    • Author(s)
      S Shintani, C Li, M Mihara, T Isikawa, M Mihara, K Nakashiro, H Hamakawa
    • Journal Title

      Oral Oncol 40(1)

      Pages: 13-20

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Gefinitib ('Iressa', ZD1839), an eppidermal growth factor receptor tyrosine kinase inhibitor, up-regulates p27KIPl and induces G1 arrest in oral squamous cell carcinoma cell lines.2004

    • Author(s)
      S Shintani, C Li, M Mihara, J Yano, N Terakado, K Nakashiro, H Hamakawa
    • Journal Title

      Oral Oncol 40(1)

      Pages: 43-51

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Basic and clinical studies on quantitative analysis of lymph node micrometastasis in oral cancer.2004

    • Author(s)
      A Onishi, K Nakashiro, M Mihara, T Sumida, H Kawamata, S Shintani, T Aida, T Tachikawa, H Hamakawa
    • Journal Title

      Oncol Rep 11(1)

      Pages: 33-39

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Overexpression of cyclooxygenase-2 is associated with radioresistance in oral squamous cell carcinoma.2004

    • Author(s)
      N Terakado, S Shintani, J Yano, C Li, M Mihara, K Nakashiro, Hamakawa H
    • Journal Title

      Oral Oncol 40(4)

      Pages: 383-389

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Growth regulated oncogene 1 expression is associated with angiogenesis and lymph node metastasis in human oral cancer.2004

    • Author(s)
      Shintani S, T.Ishikawa, T.Nonaka, C.Li, K.Nakashiro, D.T.W.Wong, H.Hamakawa
    • Journal Title

      Oncol 66(4)

      Pages: 316-322

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Skp2 and Jab1 expression are associated with inverse expression of p27KIP1 and poor prognosis in oral squamous cell carcinomas.2004

    • Author(s)
      S Shintani, C Li, M Mihara, S Hino, K Nakashiro, H Hamakawa.
    • Journal Title

      Oncol 65(4)

      Pages: 355-362

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Intraoperative real-time genetic diagnosis for sentinel node navigation surgery.2004

    • Author(s)
      H Hamakawa, A Onishi, T Sumida, N Terakado, S Hino, K Nakashiro, S Shintani
    • Journal Title

      Int J Oral Max-fac Surg 33(7)

      Pages: 670-675

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Constitutive activation of Stat3 correlates with increased expression of the c-Met/HGF receptor in oral squamous cell carcinoma..2004

    • Author(s)
      Klosek SK, Nakashiro K, Hara S, Li C, Shintani S, Hamakawa H
    • Journal Title

      Oncol Rep 12(2)

      Pages: 293-296

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Flavopiridol, a cyclin dependent kinase (CDK) inhibitor, induces apoptosis by regulating Bcl-x in oral cancer cells2003

    • Author(s)
      M.Mihara, S.Shintani, K.Nakashiro, H.Hamakawa
    • Journal Title

      Oral Oncology 39.1

      Pages: 49-55

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Enhancement of radiosensitivity in head and neck cancer cells by ZD1839 ('Iressa'), a selective epidermal growth factor receptor tyrosine kinase inhibitor2003

    • Author(s)
      Shintani S, Kiyota A, Mihara M, Sumida T, Kayahara H, Nakashiro K, Hamakawa H.
    • Journal Title

      Am J Clin Oncol 26.5

      Pages: 150-156

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Enhancement of tumor radioresponse by combined treatment with gefitinib (Iressa, ZD1839), an epidermal growth factor receptor tyrosine kinase inhibitor, is accompanied by inhibition of DNA damage repair and cell growth in oral cancer2003

    • Author(s)
      S Shintani, C Li, M Mihara, N Terakado, K Nakashiro, Hamakawa H.
    • Journal Title

      Int J Cancer 107

      Pages: 1030-1037

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Gefitinib ('Iressa'), an epidermal growth factor receptor tyrosine kinase inhibitor, mediates the inhibition of lymph node metastasis in oral cancer cells2003

    • Author(s)
      S Shintani, C Li, M Mihara, K Nakashiro, Hamakawa H.
    • Journal Title

      Cancer Lett 201.2

      Pages: 149-155

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Up-regulation of DNA-dependent protein kinase correlates with radiation resistance in oral squamous cell carcinoma2003

    • Author(s)
      S Shintani, M Mihara, C Li, Y Nakahara, K Nakashiro, Hamakawa H
    • Journal Title

      Cancer Sci 94

      Pages: 894-900

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Thiazolidinediones inhibit cell growth of human oral squamous cell carcinoma in vitro independent of peroxisome proliferator-activated receptor gamma2003

    • Author(s)
      Nakashiro K, Begum NM, Uchida D, Kawamata H, Shintani S, Sato M, Hamakawa H
    • Journal Title

      Oral Oncol 39 (8)

      Pages: 855-861

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Possible role of stromal-cell-derived factor-1/CXCR4 signaling on lymph node metastasis of oral squamous cell carcinoma2003

    • Author(s)
      Uchida D, Begum NM, Almofti A, Nakashiro K, Kawamata H, Tateishi Y, Hamakawa H, Yoshida H, Sato M
    • Journal Title

      Exp Cell Res 290 (2)

      Pages: 289-302

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Flavopiridol, a cyclin dependent kinase (CDK) inhibitor, induces apoptosis by regulating Bcl-x in oral cancer cells.2003

    • Author(s)
      M.Mihara, S.Shintani, K.Nakashiro, H.Hamakawa
    • Journal Title

      Oral Oncology 39(1)

      Pages: 49-55

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Enhancement of radiosensitivity in head and neck cancer cells by ZD1839 ('Iressa'), a selective epidermal growth factor receptor tyrosine kinase inhibitor.2003

    • Author(s)
      Shintani S, Kiyota A, Mihara M, Sumida T, Kayahara H, Nakashiro K, Hamakawa H
    • Journal Title

      Am J Clin Oncol 26(5)

      Pages: E150-E156

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Enhancement of tumor radioresponse by combined treatment with gefitinib (Iressa, ZD1839), an epidermal growth factor receptor tyrosine kinase inhibitor, is accompanied by inhibition of DNA damage repair and cell growth in oral cancer.2003

    • Author(s)
      S Shintani, C Li, M Mihara, N Terakado, K Nakashiro, Hamakawa H
    • Journal Title

      Int J Cancer 107

      Pages: 1030-1037

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Gefitinib ('Iressa'), an epidermal growth factor receptor tyrosine kinase inhibitor, mediates the inhibition of lymph node metastasis in oral cancer cells.2003

    • Author(s)
      S Shintani, C Li, M Mihara, K Nakashiro, Hamakawa H
    • Journal Title

      Cancer Lett 201(2)

      Pages: 149-155

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Up-regulation of DNA-dependent protein kinase correlates with radiation resistance in oral squamous cell carcinoma.2003

    • Author(s)
      S Shintani, M Mihara, C Li, Y Nakahara, K Nakashiro, Hamakawa H
    • Journal Title

      Cancer Sci 94

      Pages: 894-900

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Thiazolidinediones inhibit cell growth of human oral squamous cell carcinoma in vitro independent of peroxisome proliferator-activated receptor gamma.2003

    • Author(s)
      Nakashiro K, Begum NM, Uchida D, Kawamata H, Shintani S, Sato M, Hamakawa H
    • Journal Title

      Oral Oncol 39(8)

      Pages: 855-861

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Possible role of stromal-cell-derived factor-1/CXCR4 signaling on lymph node metastasis of oral squamous cell carcinoma.2003

    • Author(s)
      Uchida D, Begum NM, Almofti A, Nakashiro K, Kawamata H, Tateishi Y, Hamakawa H, Yoshida H, Sato M
    • Journal Title

      Exp Cell Res 290(2)

      Pages: 289-302

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Lymph node metastasis of oral cancer visualised in live tissue by green fluorescent protein expression2002

    • Author(s)
      S.Shintani, M.Mihara, Y.Nakahara, T.Aida, T.Tachikawa, H.Hamakawa
    • Journal Title

      Oral Oncology 38.7

      Pages: 664

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Cyclin-dependent kinase inhibitor (Roscovitine) suppresses the growth and induce apoptosis by regulating Bcl-x in head and neck squamous cell carcinoma cells2002

    • Author(s)
      Mihara M, Shintani S, Kiyota A, Matsumura T, Wong DT W.
    • Journal Title

      Int J Oncol 21

      Pages: 95-101

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Lymph node metastasis of oral cancer visualized in live tissue by green fluorescent protein expression.2002

    • Author(s)
      S.Shintani, M.Mihara, Y.Nakahara, T.Aida, T.Tachikawa, H.Hamakawa
    • Journal Title

      Oral Oncology 38(7)

      Pages: 664

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Cyclin-dependent kinase inhibitor (Roscovitine) suppresses the growth and induce apoptosis by regulating Bcl-x in head and neck squamous cell carcinoma cells.2002

    • Author(s)
      Mihara M, Shintani S, Kiyota A, Matsumura T, Wong DT W
    • Journal Title

      Int J Oncol 21

      Pages: 95-101

    • Description
      「研究成果報告書概要(欧文)」より

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Published: 2008-05-27  

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