Clinical & Experimental Metastasis

, Volume 24, Issue 8, pp 619–636 | Cite as

Lymphatic metastasis in breast cancer: importance and new insights into cellular and molecular mechanisms

  • Suzanne Eccles
  • Lenaic Paon
  • Jonathan Sleeman
Research Paper


Lymph node metastasis is the main prognosis factor in a number of malignancies, including breast carcinomas. The means by which lymph node metastases arise is not fully understood, and many questions remain about their importance in the further spread of breast cancer. Nevertheless, a number of key cellular and molecular mechanisms of lymphatic metastasis have been identified. These include induction of intra- or peri-tumoral lymphangiogenesis or co-option of existing lymphatic vessels to allow tumour cells to enter the lymphatics, although it remains to be established whether this is primarily an active or passive process. Gene expression microarrays and functional studies in vitro and in vivo, together with detailed clinical observations have identified a number of molecules that can play a role in the genesis of lymph node metastases. These include the well-recognised lymphangiogenic cytokines VEGF-C and VEGF-D as well as chemokine-receptor interactions, integrins and downstream signalling pathways. This paper briefly reviews current clinical and experimental evidence for the underlying mechanisms and significance of lymphatic metastasis in breast cancer and highlights questions that still need to be addressed.


Lymph node Metastasis Breast cancer Lymphangiogenesis Chemokines 





Blood vessel invasion


Cell adhesion molecule


Ductal carcinoma in situ


Disease-free survival


Oestrogen receptor


Focal adhesion kinase


Hypoxia inducible factor


Insulin-like growth factor 1 receptor


Insulin-like growth factor binding protein




Integrin-linked kinase


Lymphatic endothelial cell


Lymph node (metastasis)


Lymphatic vessel density


Lymphovascular invasion


Matrix metalloprotease


Microvessel density


Nitric oxide synthase


Non-steroidal anti-inflammatory drug


Non-small cell lung cancer


Overall survival


Paired box gene 5


Receptor tyrosine kinase (inhibitor)


Squamous cell carcinoma (of the head and neck)


Sentinel lymph node


Tumour associated macrophage


Urokinase plasminogen activator receptor


Vascular endothelial growth factor (receptor)



The authors acknowledge funding from the European Union Sixth Framework Program (MetaBre—LSHC-CT-2004-50304 and BRECOSM—LSHC-2004-50322), from the Cancer Research UK [CRUK] programme grant numbers CA309/A2187 and C309/A8274 (SE), from the Deutsche Forschungsgemeinschaft under the auspices of SPP 1190 “The tumour-vessel interface” and from the BMBF NGFN2 CancerNet Programme (JPS).


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Copyright information

© Springer Science+Business Media B.V. 2007

Authors and Affiliations

  1. 1.Cancer Research UK Centre for Cancer Therapeutics, McElwain LaboratoriesThe Institute of Cancer ResearchSurreyUK
  2. 2.Forschungszentrum Karlsruhe, Institut für Toxikologie und GenetikKarlsruheGermany

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