Molecular mechanisms of lymphangiogenesis in cutaneous neoplasms

• Project/Area Number: 20013032
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Ehime University
• Principal Investigator: HIRAKAWA Satoshi Ehime University, 医学部・附属病院, 講師 (50419511)
• Project Period (FY): 2008 – 2009
• Project Status: Completed (Fiscal Year 2009)
• Budget Amount: ¥18,000,000 (Direct Cost: ¥18,000,000); Fiscal Year 2009: ¥9,000,000 (Direct Cost: ¥9,000,000); Fiscal Year 2008: ¥9,000,000 (Direct Cost: ¥9,000,000)
• Keywords: 血管新生 / リンパ管新生 / 浸潤 / 転移 / 上皮-間葉転換 / 予後 / 皮膚癌 / 乳房外Paget病 / 予後因子 / 治療

Research Abstract

However, the role of nodal lymphangiogenesis in distant metastasis and in the overall survival of cancer patients remains unknown. Therefore, we investigated mechanisms that might facilitate regional and distant LN metastasis in extramammary Paget's disease (EMPD). We retrospectively analyzed the impact of tumor-induced lymphatic vessel activation on the survival of 116 patients, the largest cohort with EMPD studied to date. Nodal lymphangiogenesis was significantly increased in metastatic, compared with tumor-free LNs (P = 0.022). Increased lymphatic invasion within regional LNs was significantly associated with distant metastasis in LN (P = 0.047) and organs (P = 0.003). Thus, invasion within regional LNs is a powerful indicator of systemic tumor spread and reduced patient survival in EMPD (P = 0.0004). Lymphatic vessels associated with tumors expressed stromal cell-derived factor-1 (SDF-1), whereas CXCR4 was expressed on invasive Paget cells undergoing epithelial-mesenchymal transition (EMT)-like process. A431 cells overexpressing Snail expressed increased levels of CXCR4 in the presence of TGF-β1. Haptotactic migration assays confirmed that Snail-induced EMT-like process promotes tumor cell motility via the CXCR4-SDF-1 axis. Sinusoidal lymphatic endothelial cells and macrophages expressed SDF-1 in subcapsular sinuses of lymph nodes before Paget cell arrival. Our findings reveal that EMT-related features likely promote lymphatic metastasis of EMPD by activating the CXCR4-SDF-1 axis.

Research Products

• [Journal Article] Nodal Lymphangiogenesis and Metastasis: Role of Tumor-induced Lymphatic Vessel Activation in Extramammary Paget's Disease. (2009)
  • Author(s): Hirakawa S, Detmar M, Kerjaschki D, Nagamatsu S, Matsuo K, Tanemura A, Kamata N, Higashikawa K, Okazaki H, Kameda K, Nishida-Fukuda H, Mori H, Hanakawa Y, Sayama K, Shirakata Y, Tohyama M, Tokumaru S, Katayama I, Hashimoto K
  • Journal Title: Am J Pathol 175 Pages: 2235-48
  • Peer Reviewed
• [Journal Article] From tumor lymphangiogenesis to lymphvascular niche. (2009)
  • Author(s): Hirakawa S
  • Journal Title: Cancer Sci. 100 Pages: 83-9
  • NAID: 10025146136
  • Peer Reviewed
• [Journal Article] Living skin equivalents constructed using human amnions as a matrix. (2009)
  • Author(s): Yang L, Shirakata Y, Tokumaru S, Xiuju D, Tohyama M, Hanakawa Y, Hirakawa S, Sayama K, Hashimoto K
  • Journal Title: J Dermatol Sci. 56 Pages: 188-95
  • NAID: 10027398843
  • Peer Reviewed
• [Journal Article] IL-17 and IL-22 mediate IL-20 subfamily cytokine production in cultured keratinocytes via increased IL-22 receptor expression. (2009)
  • Author(s): Tohyama M, Hanakawa Y, Shirakata Y, Dai X, Yang L, Hirakawa S, Tokumaru S, Okazaki H, Sayama K, Hashimoto K
  • Journal Title: Eur J Immunol 39 Pages: 2779-88
  • Peer Reviewed
• [Journal Article] Nodal lymphangiogenesis : and metastasis (2009)
  • Author(s): Hirakawa, et al.
  • Journal Title: Am J Pathol 175 Pages: 2235-2248
  • Peer Reviewed
• [Journal Article] From tumor lymphangiogenesis to lymphvascular niche (2009)
  • Author(s): Hirakawa S.
  • Journal Title: Cancer sci. 100 Pages: 983-989
  • NAID: 10025146136
  • Peer Reviewed
• [Journal Article] Plasma-membrane-anchored growth factor pro-amphiregulin binds A-type lamin and regulates global transcription. (2008)
  • Author(s): Isokane M, Hieda M, Hirakawa S, Shudou M, Nakashiro K, Hashimoto K, Hamakawa H, Higashiyama S
  • Journal Title: J Cell Sci. 121 Pages: 3608-18
  • Peer Reviewed
• [Journal Article] The NF-kappaB, p38 MAPK and STAT1 pathways differentially regulate the dsRNA-mediated innate immune responses of epidermal keratinocytes. (2008)
  • Author(s): Dai X, Sayama K, Tohyama M, Shirakata Y, Yang L, Hirakawa S, Tokumaru S, Hashimoto K
  • Journal Title: Int Immunol 20 Pages: 901-9
  • Peer Reviewed
• [Journal Article] PPARγis an important transcription factor in 1α, 25-dihydroxyvitamin D3-induced involucrin expression. (2008)
  • Author(s): Dai X, Sayama K, Shirakata Y, Tokumaru S, Yang L, Tohyama M, Hirakawa S, Hanakawa Y, Hashimoto K
  • Journal Title: J Dermatol Sci. 50 Pages: 53-60
  • Peer Reviewed
• [Journal Article] From tumor lymphangiogenesis to lymphvascular niche
  • Author(s): Hirakawa S.
  • Journal Title: Cancer Sci (印刷中)
  • NAID: 10025146136
  • Peer Reviewed
• [Presentation] リンパ管新生:癌リンパ行性転移と皮膚炎症における役割 (2010)
  • Author(s): 平川聡史
  • Organizer: 第83回日本薬理学会年会シンポジウム
  • Place of Presentation: 大阪
• [Presentation] Lymph node lymphangiogenesis (2009)
  • Author(s): 平川聡史
  • Organizer: 7^<th> World Congress on Melanoma
  • Place of Presentation: オーストリアウィーン
  • Year and Date: 2009-05-15
• [Presentation] Intra-nodal lymphangiogenesis: a concept reflecting metastatic spread of tumors in the lymphatic system (2009)
  • Author(s): 平川聡史
  • Organizer: 第34回日本微小循環学会年次総会シンポジウム
  • Place of Presentation: 東京
  • Year and Date: 2009-02-21
• [Presentation] Functional role of tumor-associated lymphatic vessels in lymph node metastasis (2009)
  • Author(s): 平川聡史, 松尾恵太郎, 東川晃一郎, 鎌田伸之
  • Organizer: 第68回日本癌学会学術総会
  • Place of Presentation: 横浜
• [Presentation] Lymphatic hyperpermeability and persistent inflammation induced by cutaneous delayed-type hypersensitivity reactions in angiopoietin-related growth factor transgenic mice. (2009)
  • Author(s): Hirakawa S, Sato E, Okazaki H, Shodou M, Oike Y, Hashimoto K
  • Organizer: 39th Annual European Society for Dermatological Research (ESDR) Meeting
  • Place of Presentation: Budapest, Hungary
• [Presentation] 皮膚疾患とリンパ管新生:病態解明を目指して (2009)
  • Author(s): 平川聡史
  • Organizer: 第33回日本リンパ学会総会 シンポジウム
  • Place of Presentation: 高槻市
• [Presentation] リンパ管新生:がん組織におけるリンパ管の役割 (2009)
  • Author(s): 平川聡史, 橋本公二
  • Organizer: 第25回日本dds学会ワークショップ
  • Place of Presentation: 東京
• [Presentation] Lymph node lymphangiogenesis - a new concept in cancer metastasis. (2009)
  • Author(s): Hirakawa S
  • Organizer: Symposium in 7th World Congress on Melanoma and 5th Congress of the European Association of Dermato-Oncology (EADO)
  • Place of Presentation: Vienna, Austria
• [Presentation] リンパ管新生:乳房外Paget病におけるリンパ行性転移機序 (2009)
  • Author(s): 平川聡史, 松尾恵太郎
  • Organizer: 第7回日本臨床腫瘍学会学術集会
  • Place of Presentation: 名古屋市
• [Presentation] Lymph node lymphangiogenesis and metastasis: Role of tumor and lymphatic vessel activation in extramammary Paget disease. (2008)
  • Author(s): Hirakawa S, Matsuo K
  • Organizer: 67th Annual Meeting of the Japanese Cancer Association
  • Place of Presentation: Nagoya
  • Year and Date: 2008-10-30
• [Presentation] Lymph node lymphangiogmesis and metastasis Rale of tumor and vessel activation in extramammary Paget drsease (2008)
  • Author(s): Hirakawa S, Matsuo K.
  • Organizer: 第67回日本癌学会学術総会
  • Place of Presentation: 名古屋国際会議場
  • Year and Date: 2008-10-28
• [Presentation] Activation of tumor and nodal lymphatic vessels promotes metastasis of extramammary Paget ' s disease undergoing epithelial-mesenchymal transition. (2008)
  • Author(s): Hirakawa S, Nagamatsu S, Matsuo K, Tanemura A, Katayama I, Detmar M, Hashimoto, K
  • Organizer: UICC World Cancer Congress
  • Place of Presentation: Geneva, Switzerland
• [Presentation] Activation of tumor and nodal lymphatic vessels promotes metastasis of extramammary Paget's disease undergoing epithelial-mesenchymal transition. (2008)
  • Author(s): Hirakawa S, Nagamatsu S, Matsuo K, Tanemura A, Katayama I, Detmar M, Hashimoto, K
  • Organizer: 5th International Investigative Dermatology
  • Place of Presentation: Kyoto, Japan
• [Book] Vascular Biology.(2nd ed. Bologna J et al., eds., Textbook of Dermatology) (2008)
  • Author(s): Detmar M, Hirakawa S
  • Publisher: MOSBY ELSEVIER.