Extracellular vesicle-mediated heterogeneous communication between cancer and the lymphatic system facilitates lymphatic metastasis

Introduction The dissemination of cancer cells to organs initiates the for-mation of an aggressive cancer phenotype and is a predom-inant cause of cancer-associated death. For most epithelial cancers, lymphatic system metastasis has been characterized as the most common and earliest metastatic pathway, and the detection of metastasis in lymph nodes (LNs) often predicts poor survival among patients1. Although increasing attention is being paid to the clinical importance of LN metastasis, the underlying mechanisms have remained unclear in the past decade. Accumulating evidence suggests that the occurrence of LN metastasis is not stochastic but is a programming bio-logical event regulated by the bidirectional crosstalk between metastasis-initiating cancer cells and the tumor microenvi-ronment (TME)2. However, the regulators and patterns of cancer-TME communication in LN metastasis remain to be further explored.