The metastatic phenotype is the single most lethal phenotype which cancer displays, and once a solid tumor evolves into a metastatic phenotype prognosis-is poor. Metastasis can occur through vascular as well as lymphatic dissemination. Although lymph node metastasis is the most powerful index of prognosis, particularly in breast cancer, mechanisms underlying lymphatic metastasis have largely been overshadowed by the focus on angiogenesis and vascular dissemination. This is partly due to the unavailability, until recently, of techniques to differentiate between lymphatic and blood vessels. Similarly, while MR methods have been applied to study tumor vasculature, their application to studying lymphatic drainage and interstitial clearance is limited. The recent discovery that VEGF-C is a lymphangiogenic factor which binds to VEGFR-3 on lymphatic endothelial cells now provides an entirely new dimension to identifying and understanding lymphatic flow and lymphatic vessels in cancer metastasis. In this application from the' Weizmann Institute and Johns Hopkins, two laboratories which have been studying angiogenesis (Weizmann) and the role of vascularization and the physiological environment in cancer invasion and metastasis (Hopkins) have joined forces to understand the mechanisms and factors which contribute to lymphatic drainage and lymphatic metastasis. The effort at Weizmann will focus on understanding the impact of angiogenesis on lymphatic drain and lymphangiogenesis using a VEGF-A switchable tumor model system, dermal incisions, and transgenic VEGF-C mice. The effort at Hopkins will focus on understanding the impact of lymphatic drainage and lymphangiogenesis on tumor metastasis using human breast cancer models and their transgenic counterparts. In addition, the role of the matrix and cell-cell interactions will also be investigated. Novel MRI approaches will be developed in combination with existing state of the art MRI and 3D reconstruction capabilities to quantify lymphatic structure and function. The MRI methods will be validated with fluorescence rnicrolymphography at Weizmann and histology at Johns Hopkins. The' proposed studies will advance the understanding of factors and mechanisms regulating lymphangiogenesis and lymphatic drainage in normal tissue and in solid tumors, and will provide answers to critical questions in breast cancer metastasis.
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