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

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Abstract

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.

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Abbreviations

1°:

Primary

2°:

Secondary

BVI:

Blood vessel invasion

CAM:

Cell adhesion molecule

DCIS:

Ductal carcinoma in situ

DFS:

Disease-free survival

ER:

Oestrogen receptor

FAK:

Focal adhesion kinase

HIF:

Hypoxia inducible factor

IGF-1R:

Insulin-like growth factor 1 receptor

IGFBP:

Insulin-like growth factor binding protein

IHC:

Immunohistochemistry

ILK:

Integrin-linked kinase

LEC:

Lymphatic endothelial cell

LN(M):

Lymph node (metastasis)

LVD:

Lymphatic vessel density

LVI:

Lymphovascular invasion

MMP:

Matrix metalloprotease

MVD:

Microvessel density

NO(S):

Nitric oxide synthase

NSAID:

Non-steroidal anti-inflammatory drug

NSCLC:

Non-small cell lung cancer

OS:

Overall survival

PAX5:

Paired box gene 5

RTK(i):

Receptor tyrosine kinase (inhibitor)

SCC(HN):

Squamous cell carcinoma (of the head and neck)

SLN:

Sentinel lymph node

TAM:

Tumour associated macrophage

uPAR:

Urokinase plasminogen activator receptor

VEGF(R):

Vascular endothelial growth factor (receptor)

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Acknowledgements

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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Authors and Affiliations

  1. Cancer Research UK Centre for Cancer Therapeutics, McElwain Laboratories, The Institute of Cancer Research, Cotswold Road, Sutton, Surrey, SM2 5NG, UK

    Suzanne Eccles & Lenaic Paon

  2. Forschungszentrum Karlsruhe, Institut für Toxikologie und Genetik, Postfach 3640, 76021, Karlsruhe, Germany

    Jonathan Sleeman

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  1. Suzanne Eccles
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  2. Lenaic Paon
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Correspondence to Suzanne Eccles.

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Eccles, S., Paon, L. & Sleeman, J. Lymphatic metastasis in breast cancer: importance and new insights into cellular and molecular mechanisms. Clin Exp Metastasis 24, 619–636 (2007). https://doi.org/10.1007/s10585-007-9123-5

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