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Analysis of Tumor Angiogenesis As Regulated by Soluble Microenvironmental Cues

Tumor vascularization represents a hallmark of cancer that is modulated by the molecular interplay between vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8). Recent experimental evidence indicates that tumors exhibit differences in the spatiotemporal distribution of these factors; however, the effects of these differences on tumor angiogenesis and progression in vivo remain unclear. Specifically, in the center of the tumor VEGF concentrations are enhanced, but in the tumor periphery IL-8 concentration is highest. VEGF is secreted at relatively constant levels, while IL-8 secretion is up-regulated over time (Fischbach, et al, 2007). Furthermore, VEGF and IL-8 may promote angiogenesis by different cellular mechanisms. Both factors are known for their direct roles on endothelial cells, but IL-8 may also indirectly regulate angiogenic processes by neutrophil recruitment. Neutrophils may be implicated in the “angiogenic switch”; however, the molecular mechanisms and effects of neutrophil recruitment on tumor angiogenesis in vivo remain poorly understood. The overall goal of this work is to investigate the importance of spatiotemporal differences in VEGF and IL-8 distribution on capillary formation in vivo and to study the role of neutrophils in this process.

Strategies for non-invasive imaging into the skin of mice have been optimized (Flesken-Nikitin, et al, 2004; Larson, et al, 2003) and cell motility can be followed for hours with no apparent adverse effects (Figure 1).  We will utilize polymeric growth factor delivery strategies, MPM, and a fluorescent mouse model that will allow for visualization of endothelial cell behavior in situ. Specifically, we will design morphogen releasing delivery systems to recreate differential spatial and temporal release kinetics characteristic of tumors in vivo and will inject these polymeric matrices into the intradermal space of Tg(TIE2GFP)287Sato/J mice. The endothelial cells of these mice express GFP, allowing for analysis of their migration behavior and capillary tube formation in response to VEGF and IL-8 delivery regimens by MPM. To investigate indirect contributions of neutrophils in this process, we will perform equivalent experiments in neutrophil ablated mice. These mice will be generated by daily injections of anti-GR-1 antibodies as previously described. This work will contribute to a better understanding of the molecular and cellular mechanisms contributing to tumor angiogenesis and may ultimately lead to more efficacious anti-angiogenic therapies. 


Fischbach,C. et al. (2007) Engineering tumors with 3-D scaffolds. Nature Methods in press.

Nozawa,H., C. Chiu & D. Hanahan (2006) Infiltrating neutrophils mediate the initial angiogenic switch in a mouse model of multistage carcinogenesis. Proc. Natl. Acad. Sci U. S. A 103, 12493-12498.

Flesken-Nikitin, A., R.M. Williams, W.R. Zipfel, W.W. Webb, and A.Y. Nikitin (2004) Use of multiphoton imaging for studying cell migration in the mouse. Methods Mol Biol 294:335-346.






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