Mechanisms of Lymphatic Metastasis

Overview

Journal J Clin Invest

Specialty General Medicine

Date 2014 Mar 5

PMID 24590277

Citations 282

Authors

Sinem Karaman

Michael Detmar

Affiliations

Soon will be listed here.

Abstract

Malignant tumors release growth factors such as VEGF-C to induce lymphatic vessel expansion (lymphangiogenesis) in primary tumors and in draining sentinel LNs, thereby promoting LN metastasis. Surprising recent evidence suggests that lymphatic vessels do not merely represent passive channels for tumor spread, but that they may actively promote tumor cell recruitment to LNs, cancer stem cell survival, and immune modulation. New imaging approaches allow the sensitive visualization of the earliest LN metastases and the quantitative, noninvasive measurement of the function of tumor-draining lymphatic vessels, with potential applications in the development of biomarkers for prognosis and measurement of therapeutic response.

Citing Articles

[New systemic treatment approaches for conjunctival melanoma].

Steinberg F, Simon M, Wawer-Matos Reimer P, Rokohl A, Heindl L Ophthalmologie. 2025; .

PMID: 40067450 DOI: 10.1007/s00347-025-02207-9.

The role of tumor-derived exosomal LncRNA in tumor metastasis.

Yu Z, Fu J, Mantareva V, Blazevic I, Wu Y, Wen D Cancer Gene Ther. 2025; .

PMID: 40011710 DOI: 10.1038/s41417-024-00852-x.

AXL promotes lymphangiogenesis by amplifying VEGF-C-mediated AKT pathway.

Pirson S, Gautier-Isola M, Baudin L, Rouaud L, Vanwynsberghe A, Deroye J Cell Mol Life Sci. 2025; 82(1):95.

PMID: 40011241 PMC: 11865408. DOI: 10.1007/s00018-024-05542-3.

Lymphatic transport in anti-tumor immunity and metastasis.

Sun M, Angelillo J, Hugues S J Exp Med. 2025; 222(3).

PMID: 39969537 PMC: 11837853. DOI: 10.1084/jem.20231954.

Transcription factor A, mitochondrial promotes lymph node metastasis and lymphangiogenesis in epithelial ovarian carcinoma.

Wubuli R, Niyazi M, Han L, Aierken M, Fan L Open Med (Wars). 2025; 20(1):20241089.

PMID: 39927160 PMC: 11806237. DOI: 10.1515/med-2024-1089.

References

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

Kerjaschki D, Bago-Horvath Z, Rudas M, Sexl V, Schneckenleithner C, Wolbank S . Lipoxygenase mediates invasion of intrametastatic lymphatic vessels and propagates lymph node metastasis of human mammary carcinoma xenografts in mouse. J Clin Invest. 2011; 121(5):2000-12. PMC: 3083794. DOI: 10.1172/JCI44751. View

Kalin R, Banziger-Tobler N, Detmar M, Brandli A . An in vivo chemical library screen in Xenopus tadpoles reveals novel pathways involved in angiogenesis and lymphangiogenesis. Blood. 2009; 114(5):1110-22. PMC: 2721788. DOI: 10.1182/blood-2009-03-211771. View

Aebischer D, Iolyeva M, Halin C . The inflammatory response of lymphatic endothelium. Angiogenesis. 2013; 17(2):383-93. DOI: 10.1007/s10456-013-9404-3. View

Schacht V, Dadras S, Johnson L, Jackson D, Hong Y, Detmar M . Up-regulation of the lymphatic marker podoplanin, a mucin-type transmembrane glycoprotein, in human squamous cell carcinomas and germ cell tumors. Am J Pathol. 2005; 166(3):913-21. PMC: 1602360. DOI: 10.1016/S0002-9440(10)62311-5. View

Kaipainen A, Korhonen J, Mustonen T, van Hinsbergh V, Fang G, Dumont D . Expression of the fms-like tyrosine kinase 4 gene becomes restricted to lymphatic endothelium during development. Proc Natl Acad Sci U S A. 1995; 92(8):3566-70. PMC: 42208. DOI: 10.1073/pnas.92.8.3566. View

Shields J, Kourtis I, Tomei A, Roberts J, Swartz M . Induction of lymphoidlike stroma and immune escape by tumors that express the chemokine CCL21. Science. 2010; 328(5979):749-52. DOI: 10.1126/science.1185837. View

Mumprecht V, Detmar M . Lymphangiogenesis and cancer metastasis. J Cell Mol Med. 2009; 13(8A):1405-16. PMC: 3572232. DOI: 10.1111/j.1582-4934.2009.00834.x. View

Kawada K, Hosogi H, Sonoshita M, Sakashita H, Manabe T, Shimahara Y . Chemokine receptor CXCR3 promotes colon cancer metastasis to lymph nodes. Oncogene. 2007; 26(32):4679-88. DOI: 10.1038/sj.onc.1210267. View

10.

Meier F, Will S, Ellwanger U, Schlagenhauff B, Schittek B, Rassner G . Metastatic pathways and time courses in the orderly progression of cutaneous melanoma. Br J Dermatol. 2002; 147(1):62-70. DOI: 10.1046/j.1365-2133.2002.04867.x. View

11.

Mouta Carreira C, Nasser S, Di Tomaso E, Padera T, Boucher Y, Tomarev S . LYVE-1 is not restricted to the lymph vessels: expression in normal liver blood sinusoids and down-regulation in human liver cancer and cirrhosis. Cancer Res. 2001; 61(22):8079-84. View

12.

Christiansen A, Detmar M . Lymphangiogenesis and cancer. Genes Cancer. 2012; 2(12):1146-58. PMC: 3411123. DOI: 10.1177/1947601911423028. View

13.

Platonova N, Miquel G, Regenfuss B, Taouji S, Cursiefen C, Chevet E . Evidence for the interaction of fibroblast growth factor-2 with the lymphatic endothelial cell marker LYVE-1. Blood. 2012; 121(7):1229-37. DOI: 10.1182/blood-2012-08-450502. View

14.

Sleeman J, Nazarenko I, Thiele W . Do all roads lead to Rome? Routes to metastasis development. Int J Cancer. 2011; 128(11):2511-26. DOI: 10.1002/ijc.26027. View

15.

He Y, Rajantie I, Ilmonen M, Makinen T, Karkkainen M, Haiko P . Preexisting lymphatic endothelium but not endothelial progenitor cells are essential for tumor lymphangiogenesis and lymphatic metastasis. Cancer Res. 2004; 64(11):3737-40. DOI: 10.1158/0008-5472.CAN-04-0088. View

16.

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

17.

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

18.

Johnson L, Prevo R, Clasper S, Jackson D . Inflammation-induced uptake and degradation of the lymphatic endothelial hyaluronan receptor LYVE-1. J Biol Chem. 2007; 282(46):33671-33680. DOI: 10.1074/jbc.M702889200. View

19.

Marshall M, Rasmussen J, Tan I, Aldrich M, Adams K, Wang X . Near-Infrared Fluorescence Imaging in Humans with Indocyanine Green: A Review and Update. Open Surg Oncol J. 2012; 2(2):12-25. PMC: 3424734. DOI: 10.2174/1876504101002010012. View

20.

Kajiya K, Hirakawa S, Ma B, Drinnenberg I, Detmar M . Hepatocyte growth factor promotes lymphatic vessel formation and function. EMBO J. 2005; 24(16):2885-95. PMC: 1187946. DOI: 10.1038/sj.emboj.7600763. View