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Vascular Response to Microbeam Radiation Therapy In Vivo Using a Murine Window Chamber Tumor Model

M Dewhirst

M Dewhirst1*, A Fontanella2, G Palmer3, M Boss4, J Zhang5, M Hadsell6, S Chang7, (1) Duke University Medical Center, Durham, NC, (2) Duke University, Durham, NC, (3) Duke University, Durham, NC, (4) Duke University, Durham, NC, (5) Univ North Carolina, Chapel Hill, NC, (6) University of North Carolina at Chapel Hill, ,,(7) UNC School of Medicine, Chapel Hill, NC

TH-A-BRB-4 Thursday 8:00:00 AM - 9:55:00 AM Room: Ballroom B

Microbeam Radiation Therapy (MRT) has shown a marked tumor-specific effect. The tissue-sparing property of this unique treatment is possibly facilitated by efficient normal-vessel repair mechanisms, contrary to the catastrophic disruption of poorly regulated tumor-associated vasculature. However, significant controversy exists with regard to the role of endothelial cell death in radiation response. It is possible that the direct killing of tumor vasculature may increase radiation response within the tumor due to either oxygen/nutrient deprivation or through the “bystander effect”. The aim of this study was to characterize the vascular response to MRT in vivo using a murine window chamber model over an extended time course.

MRT treatment at various doses (300 micron single beam, 0Gy, 50Gy, 80Gy) was applied to the murine window chamber tumor model. Changes in tumor-associated vasculature after the MRT treatment utilizing intravital microscopy were profound. A robust angiogenic response was clearly present along the microbeam track in what appeared to be clusters of vessel proliferation following MRT of 50 and 80Gy. This distinctive pattern of angiogenesis was imaged through Day 7, as the irradiated track and regional microenvironment were infiltrated with a dense vascular network. In more recent experiments, we have observed infiltration of tumor cells along pre-existing vascular networks adjacent to the microbeam, to distant unirradiated sites. These types of responses were not seen in controls or in chambers following wide beam irradiation to the entire window at comparable doses. This behavior strongly suggests that the treatment is promoting epithelial mesenchymal transition, angiogenesis and local invasion. Although these observations are for microbeam treatments, the biology being observed could equally be applied to the issue of marginal miss, which is of concern for high dose conformal radiotherapy. The window chamber model provides a novel approach to direct visualization of the longitudinal vascular changes following treatment with MRT. These findings suggest that radiation induced angiogenesis at sites adjacent to the MRT beam may play an important role in modifying the tumor microenvironment. Such a response may have significant implications with regard to the understood mechanism of radiation-induced cell death.

Learning objectives:
1) Be able to describe concept of microbeam irradiation
2) understand underlying mechanisms and implications of driving angiogenic response of tumor after irradiation

This work was supported by NIH/NCI grant CA40355 and DoD grant BC083195.

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