The "Fingerprint" of Cancer Extends Beyond Solid Tumor Boundaries: Assessment With a Novel Ultrasound Imaging Approach.

Abstract

Abnormalities of microvascular morphology have been associated with tumor angiogenesis for more than a decade, and are believed to be intimately related to both tumor malignancy and response to treatment. However, the study of these vascular changes in-vivo has been challenged due to the lack of imaging approaches which can assess the microvasculature in 3-D volumes noninvasively. Here, we use contrast-enhanced "acoustic angiography" ultrasound imaging to observe and quantify heterogeneity in vascular morphology around solid tumors. Acoustic angiography, a recent advance in contrast-enhanced ultrasound imaging, generates high-resolution microvascular images unlike anything possible with standard ultrasound imaging techniques. Acoustic angiography images of a genetically engineered mouse breast cancer model were acquired to develop an image acquisition and processing routine that isolated radially expanding regions of a 3-D image from the tumor boundary to the edge of the imaging field for assessment of vascular morphology of tumor and surrounding vessels. Quantitative analysis of vessel tortuosity for the tissue surrounding tumors 3 to 7 mm in diameter revealed that tortuosity decreased in a region 6 to 10 mm from the tumor boundary, but was still significantly elevated when compared to control vasculature. Our analysis of angiogenesis-induced changes in the vasculature outside the tumor margin reveals that the extent of abnormal tortuosity extends significantly beyond the primary tumor mass. Visualization of abnormal vascular tortuosity may make acoustic angiography an invaluable tool for early tumor detection based on quantifying the vascular footprint of small tumors and a sensitive method for understanding changes in the vascular microenvironment during tumor progression.