Mechanisms of lymph node metastasis: An extracellular vesicle perspective

In several solid tumors such as breast cancer, prostate cancer, colorectal cancer or melanoma, tumor draining lymph nodes are the earliest tissues where colonization by tumor cells is detected. Lymph nodes act as sentinels of metastatic dissemination, the deadliest phase of tumor progression. Besides hematogenous dissemination, lymphatic spread of tumor cells has been demonstrated, adding more complexity to the mechanisms involved in metastasis. A network of blood and lymphatic vessels surrounds tumors providing routes for tumor soluble factors to mediate regional and long-distance effects. Additionally, extracellular vesicles (EVs), particularly small EVs/exosomes, have been shown to circulate through the blood and lymph, favoring the formation of premetastatic niches in the tumor-draining lymph nodes (TDLNs) and distant organs. In this review, we present an overview of the relevance of lymph node metastasis, the structural and immune changes occurring in TDLNs during tumor progression, and how extracellular vesicles contribute to modulating some of these alterations while promoting the formation of lymph node pre-metastatic niches.