Simian virus SV40 large T Antigen expression in the islets of Langerhans of transgenic mice results in -cell hyperproliferation, onset of new blood vessel formation and the development of highly vascularized solid tumors. Angiogenesis in the RIPTag mouse model, as well as in human cancer, is a hallmark of multistage tumorigenesis and precedes the development of solid tumors. In our study, intravital microscopy was used to monitor changes in the blood vessel phenotype, microcirculation and leukocyte adhesion during the progression from normal islets to angiogenic islets and solid tumors. In RIP1-Tag5 mice, an aberrant microangioarchitecture becomes apparent in early stages during spontaneous tumor development. Notably, the transition from normal to angiogenic islets is characterized by an increase in vessel diameter rather than vessel numbers. Thus, dilatation of existing vessels precedes vessel sprouting. Once initiated, neovascularization in angiogenic islets results in loss of vessel hierarchy and differentiation. Solid insulinomas display a higher vessel density and even more dramatic vessel heterogeneity as revealed by local "hot spots" of neovascularization and irregular vessel diameters.
Key words: intravital microscopy; multistep tumorigenesis; angiogenesis; vessel dilatation; leukocyte adhesionAngiogenesis, defined as the proliferation of endothelial cells and subsequent formation of new blood vessels from pre-existing vessels, is a characteristic feature of numerous pathological processes including cancer. 1 During tumor neovascularization, new capillaries are recruited from the microvasculature, a process that is controlled and fine-tuned by positive and negative regulators of blood vessel growth. 2,3 Tumors are known to have a distorted vessel architecture and consequently irregular flow patterns and a heterogeneous oxygen supply that results in hypoxia. 4 These parameters contribute to a unique tumor microenvironment, which in turn modulates the therapeutic responsiveness of solid tumors, e.g., towards chemotherapeutic agents or radiation therapy. 5,6 Discovery of synthetic and endogenous angiogenesis inhibitors has opened new opportunities for the design of anticancer therapeutics that specifically target the endothelial cell compartment and indirectly suppress tumor growth. [7][8][9] Initial encouraging data were obtained in mouse transplantation models. 10,11 Moreover, in a mouse model of multistage tumorigenesis, distinct anti-angiogenic drugs have been shown to be effective at different levels during tumorigenesis, ranging from the early onset of angiogenesis to ongoing neovascularization in end-stage cancer. 12 Tumor-stage dependent drug efficacy is consistent with the notion that angiogenesis is not exclusively a feature of solid tumors but an integral part of tumor development. 2 Microvascular blood vessels, which function as the interface between blood and tissue, are not only crucial for regulating nutrient delivery but mediate arrest and extravasation of leukocytes. Although the primary ...