Analysis of the microvascular morphology and hemodynamics of breast cancer in mice using SPring-8 synchrotron radiation microangiography.

Masae Torii,Masashi Inoue,Toshifumi Fukui,Hirotsugu Tsuchimochi,Tadakatsu Inagaki,James T. Pearson,Masakazu Toi,Mikiyasu Shirai,Keiji Umetani,Shotaro Kanao

doi:10.1107/s1600577517008372

Abstract

Tumor vasculature is characterized by morphological and functional abnormalities. However, analysis of the dynamics in blood flow is still challenging because of limited spatial and temporal resolution. Synchrotron radiation (SR) microangiography above the K-edge of the iodine contrast agent can provide high-contrast imaging of microvessels in time orders of milliseconds. In this study, mice bearing the human breast cancer cell lines MDAMB231 and NOTCH4 overexpression in MDAMB231 (MDAMB231NOTCH4+) and normal mice were assessed using SR microangiography. NOTCH is transmembrane protein that has crucial roles for vasculogenesis, angiogenesis and tumorigenesis, and NOTCH4 is considered to be a cause of high-flow arteriovenous shunting. A subgroup of mice received intravenous eribulin treatment, which is known to improve intratumor core circulation (MDAMB231_eribulin). Microvessel branches from approximately 200 µm to less than 20 µm in diameter were observed within the same visual field. The mean transition time (MTT) was measured as a dynamic parameter and quantitative analysis was performed. MTT in MDAMB231 was longer than that in normal tissue, and MDAMB231NOTCH4+ showed shorter MTT [5.0 ± 1.4 s, 3.6 ± 1.0 s and 3.6 ± 1.1 s (mean ± standard deviation), respectively]. After treatment, average MTT was correlated to tumor volume (r = 0.999) in MDAMB231_eribulin, while in contrast there was no correlation in MDAMB231 (r = -0.026). These changes in MTT profile are considered to be driven by the modulation of intratumoral circulation dynamics. These results demonstrate that a SR microangiography approach enables quantitative analysis of morphological and dynamic characteristics of tumor vasculature in vivo. Further studies will reveal new findings concerning vessel function in tumors.

Highlights

Cancer requires the formation of tumor stroma for their growth and progression
It has become evident that microvessel density (MVD) is significantly increased in tumor tissues compared with adjacent normal tissues, but varies remarkably between tumors
Our results reveal the characteristic properties of the tumor microvessels in mouse models with human tumor xenografts

Summary

Introduction

Cancer requires the formation of tumor stroma for their growth and progression. The interactions between cancer cells and stromal cells like vascular cells in this microenvironment are essential for determining the properties of the tumor (Joyce & Pollard, 2009; Hanahan & Coussens, 2012). MVD often provides prognostic significance (Fox et al, 1995; Uzzan et al, 2004; Choi et al, 2005) Antiangiogenic drugs such as anti-VEGF or anti-VEGF receptor antibodies are able to suppress tumor growth and progression in various types of cancers and improve progression-free survival time (Jain, 2001; Folkman, 2007). The therapeutic impact of such drugs on overall survival remains controversial (Bergers & Hanahan, 2008; Miles et al, 2010; Robert et al, 2011; Fakhrejahani & Toi, 2014; Jain, 2014) From these limited findings, we need to know more about the characteristics and biology of tumor vasculatures (Jayson et al, 2016)

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Conclusion