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.