Published online before print October 8, 2009

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(American Journal of Pathology. 2009;175:2235-2248.)
© 2009 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2009.090420

Nodal Lymphangiogenesis and Metastasis

Role of Tumor-Induced Lymphatic Vessel Activation in Extramammary Paget’s Disease

Satoshi Hirakawa^*, Michael Detmar, Dontscho Kerjaschki, Shogo Nagamatsu^*, Keitaro Matsuo^¶, Atsushi Tanemura^||, Nobuyuki Kamata^**, Koichiro Higashikawa^**, Hidenori Okazaki^*, Kenji Kameda, Hisayo Nishida-Fukuda^*, Hideki Mori^*, Yasushi Hanakawa^*, Koji Sayama^*, Yuji Shirakata^*, Mikiko Tohyama^*, Sho Tokumaru^*, Ichiro Katayama^|| and Koji Hashimoto^*

From the Departments of Dermatology^* and Bioscience, Integrated Center for Sciences, Ehime University Graduate School of Medicine, Ehime, Japan; the Department of Cell Growth and Tumor Regulation, Ehime Proteo-Medicine, Research Center, Ehime University, Ehime, Japan; the Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology, Eidgenössische Technische Hochschule Zurich, Zurich, Switzerland; the Clinical Institute of Pathology, Medical University Vienna, Vienna, Austria; the Division of Epidemiology and Prevention,^¶ Aichi Cancer Center Research Institute, Nagoya, Japan; the Department of Dermatology,|| Osaka University Graduate School of Medicine, Osaka, Japan; and the Department of Oral and Maxillofacial Surgery,^** Division of Cervico-Gnathostomatology, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan

Nodal lymphangiogenesis promotes distant lymph node (LN) metastasis in experimental cancer models. 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 transforming growth factor-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.