Nodal Lymphangiogenesis and Metastasis: Role of Tumor-induced Lymphatic Vessel Activation in Extramammary Paget's Disease

Overview

Journal Am J Pathol

Publisher Elsevier

Specialty Pathology

Date 2009 Oct 10

PMID 19815713

Citations 31

Authors

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

Koji Hashimoto

Affiliations

Soon will be listed here.

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.

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References

Chiang A, Massague J . Molecular basis of metastasis. N Engl J Med. 2008; 359(26):2814-23. PMC: 4189180. DOI: 10.1056/NEJMra0805239. View

Hirakawa S . From tumor lymphangiogenesis to lymphvascular niche. Cancer Sci. 2009; 100(6):983-9. PMC: 11158196. DOI: 10.1111/j.1349-7006.2009.01142.x. View

Moustakas A, Heldin C . Signaling networks guiding epithelial-mesenchymal transitions during embryogenesis and cancer progression. Cancer Sci. 2007; 98(10):1512-20. PMC: 11158989. DOI: 10.1111/j.1349-7006.2007.00550.x. View

Kopp H, Avecilla S, Hooper A, Rafii S . The bone marrow vascular niche: home of HSC differentiation and mobilization. Physiology (Bethesda). 2005; 20:349-56. DOI: 10.1152/physiol.00025.2005. View

Lee J, Dedhar S, Kalluri R, Thompson E . The epithelial-mesenchymal transition: new insights in signaling, development, and disease. J Cell Biol. 2006; 172(7):973-81. PMC: 2063755. DOI: 10.1083/jcb.200601018. View

Niakosari F, Kahn H, McCready D, Ghazarian D, Rotstein L, Marks A . Lymphatic invasion identified by monoclonal antibody D2-40, younger age, and ulceration: predictors of sentinel lymph node involvement in primary cutaneous melanoma. Arch Dermatol. 2008; 144(4):462-7. DOI: 10.1001/archderm.144.4.462. View

Gupta G, Massague J . Cancer metastasis: building a framework. Cell. 2006; 127(4):679-95. DOI: 10.1016/j.cell.2006.11.001. View

Hirakawa S, Hong Y, Harvey N, Schacht V, Matsuda K, Libermann T . Identification of vascular lineage-specific genes by transcriptional profiling of isolated blood vascular and lymphatic endothelial cells. Am J Pathol. 2003; 162(2):575-86. PMC: 1851142. DOI: 10.1016/S0002-9440(10)63851-5. View

van Trappen P, Pepper M . Lymphatic dissemination of tumour cells and the formation of micrometastases. Lancet Oncol. 2002; 3(1):44-52. DOI: 10.1016/s1470-2045(01)00621-0. View

10.

Wigle J, Oliver G . Prox1 function is required for the development of the murine lymphatic system. Cell. 1999; 98(6):769-78. DOI: 10.1016/s0092-8674(00)81511-1. View

11.

Rinderknecht M, Detmar M . Tumor lymphangiogenesis and melanoma metastasis. J Cell Physiol. 2008; 216(2):347-54. DOI: 10.1002/jcp.21494. View

12.

Taki M, Higashikawa K, Yoneda S, Ono S, Shigeishi H, Nagayama M . Up-regulation of stromal cell-derived factor-1alpha and its receptor CXCR4 expression accompanied with epithelial-mesenchymal transition in human oral squamous cell carcinoma. Oncol Rep. 2008; 19(4):993-8. View

13.

Skobe M, Hawighorst T, Jackson D, Prevo R, Janes L, Velasco P . Induction of tumor lymphangiogenesis by VEGF-C promotes breast cancer metastasis. Nat Med. 2001; 7(2):192-8. DOI: 10.1038/84643. View

14.

Stacker S, Caesar C, Baldwin M, Thornton G, Williams R, Prevo R . VEGF-D promotes the metastatic spread of tumor cells via the lymphatics. Nat Med. 2001; 7(2):186-91. DOI: 10.1038/84635. View

15.

Petrova T, Bono P, Holnthoner W, Chesnes J, Pytowski B, Sihto H . VEGFR-3 expression is restricted to blood and lymphatic vessels in solid tumors. Cancer Cell. 2008; 13(6):554-6. DOI: 10.1016/j.ccr.2008.04.022. View

16.

Arai J, Yasukawa M, Yakushijin Y, Miyazaki T, Fujita S . Stromal cells in lymph nodes attract B-lymphoma cells via production of stromal cell-derived factor-1. Eur J Haematol. 2000; 64(5):323-32. DOI: 10.1034/j.1600-0609.2000.90147.x. View

17.

He Y, Kozaki K, Karpanen T, Koshikawa K, Yla-Herttuala S, Takahashi T . Suppression of tumor lymphangiogenesis and lymph node metastasis by blocking vascular endothelial growth factor receptor 3 signaling. J Natl Cancer Inst. 2002; 94(11):819-25. DOI: 10.1093/jnci/94.11.819. View

18.

Schoppmann S, Birner P, Stockl J, Kalt R, Ullrich R, Caucig C . Tumor-associated macrophages express lymphatic endothelial growth factors and are related to peritumoral lymphangiogenesis. Am J Pathol. 2002; 161(3):947-56. PMC: 1867252. DOI: 10.1016/S0002-9440(10)64255-1. View

19.

Doeden K, Ma Z, Narasimhan B, Swetter S, Detmar M, Dadras S . Lymphatic invasion in cutaneous melanoma is associated with sentinel lymph node metastasis. J Cutan Pathol. 2008; 36(7):772-80. DOI: 10.1111/j.1600-0560.2008.01166.x. View

20.

Calabrese C, Poppleton H, Kocak M, Hogg T, Fuller C, Hamner B . A perivascular niche for brain tumor stem cells. Cancer Cell. 2007; 11(1):69-82. DOI: 10.1016/j.ccr.2006.11.020. View