B Lymphocytes Promote Lymphogenous Metastasis of Lymphoma and Melanoma

The prognosis of patients with many types of cancers correlates with the degree of metastasis to regional lymph nodes (LNs) and vital organs. However, the mechanisms and route of cancer cell metastasis are still unclear. Previous studies determined that B-cell accumulation in tumor-draining LNs (TDLNs) induces lymphatic sinus growth (lymphangiogenesis) and increases lymph flow, which could actively promote tumor dissemination through the lymphatic system. Using young Eµ-c-Myc mice that feature LN B-cell expansion as hosts for tumor transplants, we show that subcutaneously implanted lymphomas or melanomas preferentially spread to TDLNs over non-TDLNs, thus demonstrating that these tumors initially metastasize through lymphatic rather than through hematogenous routes. In addition, the rate and amount of tumor dissemination is greater in Eµ-c-Myc mice versus wild-type hosts, which correlates with LN B-cell accumulation and lymphangiogenesis in Eµ-c-Myc hosts. The increased lymphatic dissemination in Eµ-c-Myc hosts is further associated with rapid hematogenous tumor spread of subcutaneously implanted lymphomas, suggesting that TDLN metastasis secondarily drives lymphoma spread to distant organs. In contrast, after intravenous tumor cell injection, spleen metastasis of lymphoma cells or lung metastasis of melanoma cells is similar in Eµ-c-Myc and wild-type hosts. These studies demonstrate that the effect of Eµ-c-Myc hosts to promote metastasis is limited to the lymphatic route of dissemination. TDLN B-cell accumulation, in association with lymphangiogenesis and increased lymph flow, thus significantly contributes to dissemination of lymphomas and solid tumors, providing new targets for therapeutic intervention to block metastasis.