was inadvertently switched during the revision process with a previously published figure (1) showing results on B16 melanoma cells. The correct figure, summarizing the results on human MeWO melanoma cells transfected with ␣1,3-fucosyltransferase (FTIII), appears below. We apologize for any confusion caused by this mistake.

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. Inhibition of VEGFR-3 activation more potently suppressed regional and distant metastases than inactivation of VEGFR-2, although VEGFR-2 blockade was more effective in inhibiting angiogenesis and tumor growth. Despite prominent proliferation, metastases were not vascularized in any of the control and treatment groups, indicating that the growth of metastases was not dependent on angiogenesis at the secondary site for the duration of the experiment. Systemic treatment with either VEGFR-2 or VEGFR-3 antagonistic antibodies suppressed tumor lymphangiogenesis, indicating that VEGFR-3 signaling affects the rate of tumor cell entry into lymphatic vessels through both lymphangiogenesis-dependent and independent mechanisms. Combination treatment with the anti-VEGFR-2 and anti-VEGFR-3 antibodies more potently decreased lymph node and lung metastases than each antibody alone. These results validate the concept of targeting the lymphatic dissemination and thereby very early steps of the metastatic process for metastasis control and suggest that a combination therapy with antiangiogenic agents may be a particularly promising approach for controlling metastases. (Cancer Res 2006; 66(5): 2650-7)

Regeneration of lymphatic vessels is important for treatment of various disorders of lymphatic system and for restoration of lymphatic function after surgery. We have developed a method for generating a human 3D lymphatic vascular construct. In this system, human lymphatic endothelial cells, co-cultured with fibroblasts, spontaneously organized into a stable 3D lymphatic capillary network without the use of any exogenous factors. In vitro-generated lymphatic capillaries exhibited the major molecular and ultra-structural features of native, human lymphatic microvasculature: branches in the three dimensions, wide lumen, blind ends, overlapping borders, adherens and tight junctions, anchoring filaments, lack of mural cells, and poorly developed basement membrane. Furthermore, we show that fibroblast-derived VEGF-C and HGF cooperate in the formation of lymphatic vasculature by activating ERK1/2 signaling, and demonstrate distinct functions of HGF/c-Met and VEGF-C/VEGFR-3 in lymphangiogenesis. This lymphatic vascular construct is expected to facilitate studies of lymphangiogenesis in vitro and it holds promise as a strategy for regeneration of lymphatic vessels and treatment of lymphatic disorders in various conditions.

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