Imaging Angiogenesis, Inflammation, and Metastasis in the Tumor Microenvironment with Magnetic Resonance Imaging

Sébastien Serres, Emma R. O'Brien, and Nicola R. Sibson

Abstract With the development of new imaging techniques, the potential for probing the molecular, cellular, and structural components of the tumor microenvironment in situ has increased dramatically. A multitude of imaging modalities have been successfully employed to probe different aspects of the tumor microenvironment, including expression of molecules, cell motion, cellularity, vessel permeability, vascular perfusion, metabolic and physiological changes, apoptosis, and inflammation. This chapter focuses on the most recent advances in magnetic resonance imaging methods, which offer a number of advantages over other methodologies, including high spatial resolution and the use of nonionizing radiation, as well as the use of such methods in the context of primary and secondary brain tumors. It also highlights how they can be used to assess the molecular and cellular changes in the tumor microenvironment in response to therapy.

Keywords Magnetic resonance imaging • Cancer • Angiogenesis • Vasculature • Inflammation • Metastasis • Tumour microenvironment

Introduction

It has become increasingly apparent that cancer cells interact extensively with their environment, signaling to both stromal cells and the immune system, as well as the vasculature. It is critical to note that cancer cells seem to be able to exploit their microenvironment through these interactions to gain a growth advantage, from the induction of angiogenesis to shifts in metabolism (as illustrated in Fig. 12.1). The complex interactions between tumor cells and their surrounding environment are best studied in preclinical models, and considerable progress has been made in recent years in the development of new imaging techniques to probe the molecular and structural constituents of the tumor microenvironment (TME) in vivo. From cellular to more macroscopic changes, imaging techniques can provide information about the

Fig. 12.1 The tumor microenvironment (TME). The TME encompasses a complex interaction between cancer cells and other cell populations, including endothelial cells, stromal fibroblasts, tumor-associated macrophages, myeloid-derived suppressor cells, mesenchymal stem cells, lymphocytes, and neutrophils. During tumor growth, vascular endothelial growth factor is released and drives angiogenesis. The oncologic phosphoinositide 3-kinase/Akt/mammalian target of rapamycin signaling pathway enables stabilization of hypoxia-inducible factors, which drives hypoxia, metabolic shift, and resistance to cell death. At the same time, formation of new blood vessels and release of chemokines and cytokines induce inflammation in the TME, which can drive tumor invasion and metastasis to distant organs. TAMs and cell adhesion molecules are pivotal in the formation of metastases. (Figure based on Hanahan and Weinberg 2011)

expression of molecules, cell motion, cellularity, vessel permeability, vascular perfusion, metabolic and physiological changes, apoptosis, and inflammation in the TME. A multitude of imaging modalities have been successfully employed to probe the TME, including computed tomography, positron emission tomography (PET), single-photon emission computed tomography (SPECT), ultrasound, optical imaging, and magnetic resonance imaging (MRI). While all of these modalities can be used in either a preclinical or clinical setting to obtain insight into the TME, there are both advantages and limitations of each. For example, PET and SPECT provide high sensitivity, but they are limited by the use of radioisotopes and, compared to MRI, offer relatively low spatial resolution. Other modalities such as ultrasound and bioluminescence imaging have poor depth penetration, whereas invasive imaging modalities such as near-infrared light and fluorescence imaging are limited in their translation to the clinic (Brindle 2008; Weissleder and Pittet 2008). In comparison, magnetic resonance (MR) methodologies offer a number of advantages, including high spatial resolution and the use of nonionizing radiation. Thus, this chapter focuses on the development of MR-based techniques for imaging and probing the TME, with particular emphasis on inflammation, angiogenesis, and metastasis. We consider these approaches primarily in the context of the brain, although many are more widely applicable to the TME in general. Finally, we highlight how such modalities can be used to assess the molecular and cellular changes in the TME in

response to therapy.