Tumor cell entry into the lymph node is controlled by CCL1 chemokine expressed by lymph node lymphatic sinuses.

Lymphatic vessels are thought to contribute to metastasis primarily by serving as a transportation system. It is widely believed that tumor cells enter lymph nodes passively by the flow of lymph. We demonstrate that lymph node lymphatic sinuses control tumor cell entry into the lymph node, which requires active tumor cell migration.

MAP kinase pathway-dependent phosphorylation of the L1-CAM ankyrin binding site regulates neuronal growth.

The growth of neuronal processes depends critically on the function of adhesion proteins that link extracellular ligands to the cytoskeleton. The neuronal adhesion protein L1-CAM serves as a receptor for nerve growth-promoting proteins, a process that is inhibited by the interaction between L1-CAM and the cytoskeleton adaptor ankyrin. Using a novel reporter based on intramolecular bioluminescence resonance energy transfer, we have determined that the MAP kinase pathway regulates the phosphorylation of the FIGQY motif in the adhesion protein L1-CAM and its interaction with ankyrin B.

Inhibition of VEGFR-3 activation with the antagonistic antibody more potently suppresses lymph node and distant metastases than inactivation of VEGFR-2.

Lymph nodes are the first site of metastases for most types of cancer, and lymph node status is a key indicator of patient prognosis. Induction of tumor lymphangiogenesis by vascular endothelial growth factor-C (VEGF-C) has been shown to play an important role in promoting tumor metastases to lymph nodes. Here, we employed receptor-specific antagonist antibodies in an orthotopic spontaneous breast cancer metastasis model to provide direct evidence for the key role of VEGFR-3 activation in metastasis.

Ankyrin binding mediates L1CAM interactions with static components of the cytoskeleton and inhibits retrograde movement of L1CAM on the cell surface.

The function of adhesion receptors in both cell adhesion and migration depends critically on interactions with the cytoskeleton. During cell adhesion, cytoskeletal interactions stabilize receptors to strengthen adhesive contacts. In contrast, during cell migration, adhesion proteins are believed to interact with dynamic components of the cytoskeleton, permitting the transmission of traction forces through the receptor to the extracellular environment.

Lymphatic vessel activation in cancer.

Metastasis of most cancers occurs primarily through the lymphatic system, and the extent of lymph node involvement is the most important prognostic indicator. While the importance of the lymphatic system as a pathway for metastasis has been well recognized, there is very little information available about the mechanisms by which tumor cells interact with the lymphatics. Recently, production of the lymphangiogenic factor VEGF-C has been detected in tumors, and the significance of VEGF-C-mediated lymphangiogenesis for tumor metastasis has been demonstrated.