title: Nodal lymphangiogenesis and metastasis: Role of tumor-induced lymphatic vessel activation in extramammary Paget's disease.
abstract: 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-beta1. 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.
authors.affiliation: Department of Dermatology, Integrated Center for Sciences, Ehime University, Japan. satoshi2@m.ehime-u.ac.jp
authors.forename: Satoshi
authors.initials: S
authors.lastname: Hirakawa
authors.forename: Michael
authors.initials: M
authors.lastname: Detmar
authors.forename: Dontscho
authors.initials: D
authors.lastname: Kerjaschki
authors.forename: Shogo
authors.initials: S
authors.lastname: Nagamatsu
authors.forename: Keitaro
authors.initials: K
authors.lastname: Matsuo
authors.forename: Atsushi
authors.initials: A
authors.lastname: Tanemura
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Kamata
authors.forename: Koichiro
authors.initials: K
authors.lastname: Higashikawa
authors.forename: Hidenori
authors.initials: H
authors.lastname: Okazaki
authors.forename: Kenji
authors.initials: K
authors.lastname: Kameda
authors.forename: Hisayo
authors.initials: H
authors.lastname: Nishida-Fukuda
authors.forename: Hideki
authors.initials: H
authors.lastname: Mori
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Hanakawa
authors.forename: Koji
authors.initials: K
authors.lastname: Sayama
authors.forename: Yuji
authors.initials: Y
authors.lastname: Shirakata
authors.forename: Mikiko
authors.initials: M
authors.lastname: Tohyama
authors.forename: Sho
authors.initials: S
authors.lastname: Tokumaru
authors.forename: Ichiro
authors.initials: I
authors.lastname: Katayama
authors.forename: Koji
authors.initials: K
authors.lastname: Hashimoto
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000235:genetics / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology / Q000502:physiology; D005260:Female; D006801:Humans; D008198:Lymph Nodes / Q000098:blood supply / Q000473:pathology; D042583:Lymphangiogenesis / Q000502:physiology*; D008207:Lymphatic Metastasis / Q000473:pathology*; D042601:Lymphatic Vessels / Q000473:pathology / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D010145:Paget Disease, Extramammary / Q000175:diagnosis / Q000378:metabolism / Q000473:pathology; D011379:Prognosis; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism; D012189:Retrospective Studies; D012867:Skin / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D015996:Survival Rate
chemical_list: C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D019718:Receptors, CXCR4