Nodal lymphangiogenesis and metastasis: Role of tumor-induced lymphatic vessel activation in extramammary Paget's disease.
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.
Hirakawa
Satoshi
S
Department of Dermatology, Integrated Center for Sciences, Ehime University, Japan. satoshi2@m.ehime-u.ac.jp
Detmar
Michael
M
Kerjaschki
Dontscho
D
Nagamatsu
Shogo
S
Matsuo
Keitaro
K
Tanemura
Atsushi
A
Kamata
Nobuyuki
N
Higashikawa
Koichiro
K
Okazaki
Hidenori
H
Kameda
Kenji
K
Nishida-Fukuda
Hisayo
H
Mori
Hideki
H
Hanakawa
Yasushi
Y
Sayama
Koji
K
Shirakata
Yuji
Y
Tohyama
Mikiko
M
Tokumaru
Sho
S
Katayama
Ichiro
I
Hashimoto
Koji
K
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
C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D019718:Receptors, CXCR4