Molecular mechanisms of lymphangiogenesis in cutaneous neoplasms
| Project/Area Number |
20013032
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| Research Category |
Grant-in-Aid for Scientific Research on Priority Areas
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| Allocation Type | Single-year Grants |
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| Review Section |
Biological Sciences
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| Research Institution | Ehime University |
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Principal Investigator |
HIRAKAWA Satoshi Ehime University, 医学部・附属病院, 講師 (50419511)
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| Project Period (FY) |
2008 – 2009
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| Project Status |
Completed (Fiscal Year 2009)
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| Budget Amount *help |
¥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)
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| 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 |
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| 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.
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Report
(3 results)
Research Products
(24 results)
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[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
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Journal Title
Am J Pathol 175
Pages: 2235-48
Related Report
Peer Reviewed
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