Metastasis is a frequent and lethal complication of cancer. Vascular endothelial growth factor‐C (VEGF‐C) is a recently described lymphangiogenic factor. Increased expression of VEGF‐C in primary tumours correlates with dissemination of tumour cells to regional lymph nodes. However, a direct role for VEGF‐C in tumour lymphangiogenesis and subsequent metastasis has yet to be demonstrated. Here we report the establishment of transgenic mice in which VEGF‐C expression, driven by the rat insulin promoter (Rip), is targeted to β‐cells of the endocrine pancreas. In contrast to wild‐type mice, which lack peri‐insular lymphatics, RipVEGF‐C transgenics develop an extensive network of lymphatics around the islets of Langerhans. These mice were crossed with Rip1Tag2 mice, which develop pancreatic β‐cell tumours that are neither lymphangiogenic nor metastatic. Double‐transgenic mice formed tumours surrounded by well developed lymphatics, which frequently contained tumour cell masses of β‐cell origin. These mice frequently developed pancreatic lymph node metastases. Our findings demonstrate that VEGF‐C‐induced lymphangiogenesis mediates tumour cell dissemination and the formation of lymph node metastases.

The formation of new blood vessels (angiogenesis) is critical for the growth of tumours and is a dominant feature in various angiogenic diseases such as diabetic retinopathy, arthritis, haemangiomas and psoriasis. Recognition of the potential therapeutic benefits of controlling pathological angiogenesis has led to a search for angiogenesis inhibitors. Here we report that 2-methoxyoestradiol, an endogenous oestrogen metabolite of previously unknown function, is a potent inhibitor of endothelial cell proliferation and migration as well as angiogenesis in vitro. Moreover, when administered orally in mice, it strongly inhibits the neovascularization of solid tumors and suppresses their growth. Unlike the angiostatic steroids of corticoid structure, it does not require the co-administration of heparin or sulphated cyclodextrins for activity. Thus, 2-methoxyoestradiol is the first steroid to have high antiangiogenic activity by itself. Our results suggest that this compound may have therapeutic potential in cancer and other angiogenic diseases.

Abstract-Extracellular proteolysis is an absolute requirement for new blood vessel formation (angiogenesis). This review examines the role of the matrix metalloproteinase (MMP) and plasminogen activator (PA)-plasmin systems during angiogenesis. Specifically, a role for gelatinases (MMP-2, MMP-9), membrane-type 1 MMP , the urokinase-type PA receptor, and PA inhibitor 1 has been clearly defined in a number of model systems. The MMP and PA-plasmin systems have also been implicated in experimental vascular tumor formation, and their role during this process will be examined. Antiproteolysis, particularly in the context of angiogenesis, has become a key target in therapeutic strategies aimed at inhibiting tumor growth and other diseases associated with neovascularization. Key Words: extracellular matrix Ⅲ endothelium Ⅲ metalloproteinase Ⅲ plasminogen Ⅲ cancer I t is firmly established that angiogenesis is an absolute requirement for the growth of normal and neoplastic tissues. 1 Many biological processes, including angiogenesis, depend on tightly controlled interactions between cells and the extracellular matrix (ECM). These interactions are mediated by (1) integral membrane proteins, including integrins, which provide a link between the ECM and the cytoskeleton, and (2) extracellular proteinases and their inhibitors, which mediate focal degradation of components of the ECM, some of which (eg, the fibrillar collagens) are highly resistant to broad-spectrum proteases. Most of the relevant extracellular proteolytic enzymes belong to one of two families: the serine proteases, in particular, the plasminogen activator (PA)-plasmin system, and the matrix metalloproteinases (MMPs). [2][3][4] Like most other biological processes, angiogenesis is the result of subtle and often complex interactions between regulatory and effector molecules. To facilitate its analysis, it is useful to divide angiogenesis into a phase of activation (sprouting) and a phase of resolution. The phase of activation encompasses (1) increased vascular permeability and extravascular fibrin deposition; (2) vessel wall disassembly; (3) basement membrane degradation; (4) cell migration and ECM invasion; (5) endothelial cell proliferation; and (6) capillary lumen formation. The phase of resolution includes (1) inhibition of endothelial cell proliferation; (2) cessation of cell migration; (3) basement membrane reconstitution; (4) junctional complex maturation; and (5) vessel wall assembly, including recruitment and differentiation of smooth muscle cells and pericytes. Implicit in the definition of the resolution phase is the establishment of blood flow in the newly formed vessel. 1 Extracellular proteolysis has been implicated in many of these processes, including basement membrane degradation, cell migration/ECM invasion, and capillary lumen formation (the Table). 5 The classic descriptions by Clark and Clark in 1939 6 of new blood vessel formation in transparent chambers in the rabbit ear clearly demonstrate the production of fibrinolytic activity by growi...

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