Quantification of tumor angiogenesis with contrast-enhanced x-ray imaging in preclinical studies: a review

Abstract

Tissue contrast is a major challenge in the application of computed tomography (CT) and microcomputed tomography (micro-CT) techniques for imaging cancer. Contrast medium is used in order to enhance contrast of certain organs of interest, as well as tumors. Several types of contrast media have been used to assess tumor vasculature, perfusion and angiogenesis in preclinical studies. In general, low molecular weight contrast media have been used to characterize the first pass vascular dynamics of tumors with fast CT systems, while blood pool agents have been preferred to explore the delayed vascular dynamics with micro-CT systems. Together, these approaches provide qualitative, semi-quantitative, and quantitative information of the vascular architecture and vascular functionality of tumors in the preclinical scenario. Herein, we present an overview of contrast media, imaging techniques, image analysis methods, and quantitative parameters that have been used to evaluate tumor angiogenesis in vivo in recent preclinical studies. Preclinical applications on lesion detection and characterization, evaluation of vascular parameters as prognostic and predictive biomarkers, and evaluation of treatment response are also reviewed. These applications have demonstrated the potential of contrast-enhanced x-ray imaging to provide, in a noninvasive manner, a landscape of the spatial and temporal heterogeneity of the angiogenic process underlying tumor development.

Quantitative Imaging Parameters of Contrast-Enhanced Micro-Computed Tomography Correlate with Angiogenesis and Necrosis in a Subcutaneous C6 Glioma Model

“…Mean attenuation was also significantly higher in the aorta than in kidney in HE images. These differences were expected since it is known that the clinical contrast agent used with the SE protocol is cleared via the kidneys, while the blood pool contrast agent used with the DE protocol is cleared via the liver and spleen [ 7 ].…”

“…Another limitation in our study was related to the radiation dose inherent to X-ray imaging. The absorbed dose could cause a damage to the animals if it is not properly quantified and optimized; moreover, it can also bias the study by affecting the development of the tumor under evaluation [ 7 ]. In order to limit the effects of the dose delivered in our studies, we previously optimized the radiological parameters for image acquisition that provided the highest image quality and the lowest radiation dose to the animals [ 25 ].…”

“…CE X-ray imaging techniques have been used to assess the association of quantitative imaging parameters with histological biomarkers of angiogenesis in preclinical studies with animals [ 7 ]. Dynamic contrast-enhanced (DCE) imaging with clinical CT scanners, i.e., perfusion CT, has been the most used CE X-ray imaging technique to study angiogenesis in animal models of cancer [ 8 , 9 , 10 , 11 ].…”

Sensitive imaging of intact microvessels in vivo with synchrotron radiation

“…Early stages of diseases, including stroke, hypertension, angiogenesis of tumours, spinal cord injuries, etc., are closely associated with the lesions of microvasculature (Ayala-Domínguez & Brandan, 2018;Cao et al, 2019;Gu et al, 2019;Guan et al, 2012;Kidoguchi et al, 2006;Kiessling et al, 2004;Li et al, 2019;Lin et al, 2015;Liu et al, 2010;Tokunaga et al, 2018;Umetani et al, 2007;Wang et al, 2017Wang et al, , 2019. Rodent models of human vascular diseases are extensively used for the preclinical investigation of the disease evolution and therapy.…”

“…Non-intrusive and precise imaging for tumour angiogenesis is critical in the accurate assessment of cancer diagnosis and prognosis. X-ray microtomography is now the dominant method for the studies of angiogenesis in vitro, but X-ray imaging modalities applicable to the in vivo visualization of the microvessels are quite limited (Ayala-Domínguez & Brandan, 2018;Gu et al, 2019;Kiessling et al, 2004;Li et al, 2019;Liu et al, 2010). Stroke and hypertension are closely related to the subtle change of microvessels but current X-ray imaging methods still suffer from insufficient imaging resolution for the dynamical and direct observation of rodent cerebrovascular alterations in vivo (Guan et al, 2012;Kidoguchi et al, 2006;Lin et al, 2015;Umetani et al, 2007;Wang et al, 2017Wang et al, , 2019Yuan et al, 2013).…”