Preparing the “soil”: The primary tumor induces vasculature reorganization in the sentinel lymph node prior to the arrival of metastatic cancer cells Free

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Sentinel lymph node metastasis is the first step in the spreading of cancer in many malignancies. Tumor-reactive lymphadenopathy in sentinel lymph nodes has been observed for decades, but alterations of the lymphatic channels and vasculature in these nodes prior to the arrival of metastatic tumor cells remain unexplored. Using animal models, we show here that before the establishment of metastasis in the sentinel lymph node, there are reorganizations of the lymphatic channels and the vasculature. The node becomes a blood vessel- and lymph vessel/sinus-enriched organ prior to metastasis. The newly emerged blood vessels inside the sentinel lymph node before metastasis are functioning vessels proven by ultrasonography examination. The enlargement of the lymph sinuses is correlated with the primary tumor weight. The newly emerged functional blood vessels develop from high endothelial venules, in which the proliferation rate of the endothelial cells is also significantly increased. Similar alterations of the high endothelial venules are also characterized in the axillary lymph nodes from human breast cancer patients without the evidence of metastasis. The alterations of the vasculature and lymph channel in the sentinel lymph node under tumorous condition are very different from compared to that of endotoxin-induced lymphadenopathy. Moreover, the altered high endothelial venules can further integrate into tumor vasculature after the arrival of cancer cells, nurturing the secondary tumor and being the mother vessels inside the metastatic lesion. These findings support the hypothesis that modification of the microenvironment for a secondary tumor (i.e., vasculature reorganization in the sentinel lymph node) can be initiated by a primary tumor before and independent of the physical presence of metastatic cancer cells.