Induced lymphatic sinus hyperplasia in sentinel lymph nodes by VEGF-C as the earliest premetastatic indicator

Research on tumor-induced lymphangiogenesis has predominantly focused onalterations and abnormal growth of peritumoral and intratumoral lymphatic vessels.However, recent evidence indicates that lymphangiogenesis of sentinel lymph nodesmight also contribute to cancer progression. In clinical oncology, the sentinellymph nodes play an important role in diagnosis, staging and management of disease.The prognostic value that may be placed in the analysis of various parametersin tumor-free lymph nodes is still under debate. We, therefore, chose to investigategenetically fluorescent MDA-MB-435/green fluorescent protein human cancer cellstransfected to overexpress VEGF-C in a nude mouse model and investigated metastasis,lymph node lymphangiogenesis, lymph node angiogenesis and size of sentinel lymphnodes. The nature of MDA-MB-435, identified as a breast cancer cell line for severaldecades, has recently been reidentified as being from melanoma origin. Vascularendothelial growth factor-C overexpression induced early metastasis and significantlyincreased the lymphatic vessel area in sentinel lymph nodes even before the tumormetastasis. At early time-points, expansion of the lymphatic network was observedeven though no difference of blood vessel area and lymph node size was detected.These results suggest that primary tumors -via secretion of VEGF-C- can inducehyperplasia of the sentinel lymph node lymphatic vessel network and thereby promotetheir further spread. In cases of tumor-free lymph nodes the increased lymphaticnetwork of sentinel lymph nodes is a very early premetastatic sign and may providea new prognostic indicator and target for aggressive diseases.