Molecular imaging of the tumor microenvironment☆
Graphical abstract
Introduction
The tumor microenvironment (TME) is a complex physical and biochemical system that plays an important role in tumor initiation, progression, metastasis, and drug resistance [1], [2]. The TME is significantly different from normal tissues, and is characterized by altered functions of molecules in the extracellular matrix (ECM), vascular and lymphatic networks, and abnormal phenotypes of cells and tumor-associated macrophages. In addition, the TME displays abnormal physiologic conditions such as hypoxia, acidic extracellular pH, and increased interstitial fluid pressure. It is evidenced that tumor diversity and aggressiveness are associated with the nature of their microenvironmental composition, biochemical properties, architecture, and physical properties [3]. The TME also contributes significantly to drug resistance by hindering the tissue penetration of drug molecules or by directly influencing the sensitivity of targeting cells [4], [5], [6]. Therefore, understanding of the dynamic changes in the TME can provide new avenues for designing novel diagnostics and therapeutics for cancer detection and diagnosis, treatment, and assessment of therapeutic response.
Molecular imaging allows for the detection and visualization of cancer-related biomarkers in tumor [7], [8]. It can enable the early and accurate detection of cancer, facilitating the use of molecular signatures to tailor effective and personalized therapies for improved patient survival. In addition, molecular imaging has the potential to provide noninvasive assessment of the TME during tumor development and proliferation. While the TME is continually changing in landscape, biomolecules in TME are generally stable in different tumor types, thus making them suitable molecular imaging targets for a broad range of tumors [3].
Currently, targeted cancer therapy and imaging are mostly focused on the biomarkers of cancer cells. Nevertheless, targeting and re-modulation of the TME has been increasingly applied in designing novel therapies [9]. Molecular imaging of the TME will play an essential role in understanding the responses, mechanisms, and efficacy of these new therapies [10]. It will also enable the detection of the “premetastatic niche”, facilitating the prediction of cancer metastatic sites even before the arrival of cancer cells [11]. This approach is advantageous because it allows for the precise diagnosis of cancer by detecting factors (e.g., hypoxia) that lead to TME heterogeneity, local recurrence, and metastasis. Thus, molecular imaging of the TME provides for the early, differential diagnosis of cancer, and may facilitate the discovery and development of new effective cancer therapies [12], [13].
Cancer molecular imaging employs two key components: (1) imaging modalities such as magnetic resonance imaging (MRI), computed tomography (CT), positron emission tomography imaging (PET), ultrasonography, and optical imaging [14]; and (2) imaging probes or contrast agents, which are utilized to target, detect, and visualize cancer biomarkers [15], [16], [17], [18]. The design and development of imaging agents with high sensitivity, specificity, and low toxicity as well as a broad applicability are critical for accurate molecular imaging. This review summarizes the principles and strategies of recent advances in developing TME-targeted molecular imaging technologies for early cancer detection and diagnosis (Fig. 1).
Section snippets
Biomarkers in TME
The TME, which constitutes a dynamic network of non-cancerous cells, blood and lymphatic vessels, ECM proteins and enzymes, and immune components, regulates tumor progression, metastasis, and drug resistance [3]. In 1889, English surgeon Stephen Paget first proposed that the TME acts as “soil” for the tumor cell “seed”, explaining the nonrandom pattern of cancer metastasis [19]. It is now proved that the crosstalk between the TME and cancer cells is important in regulating tumor growth [20],
Molecular imaging of ECM proteins
The tumor ECM is highly deregulated and composed of distinct components, including modified collagens, fibrin, fibronectin, tenascin-C and laminins with different biochemical and physical properties [88]. During cancer formation, the ECM undergoes considerable remodeling to facilitate cancer initiation, progression, and invasion [89], promote angiogenesis [90], and adapt to the immune system [91]. For example, collagen has 28 different subtypes, is a major component of ECM, and makes up 30% of
Molecular imaging of tumor physiological microenvironment
The physiology of the TME is different from that of surrounding normal tissues. Insufficient and defective vascular structures of the tumor are often inadequate in supplying the nutrition necessary for tumor progression. This leads to a deficiency of oxygen and other nutrients, decreased pH, hypoxia, and increased interstitial fluid pressure. These unique characteristics of the TME strongly relate to tumor progression, metastasis, and recurrence as well as resistance to therapy. Therapeutic
Molecular imaging of tumor vasculature
The tumor vasculature is one of the most widely studied characteristics of the TME. It was first hypothesized by Judah Folkman in 1971 that solid tumors have a limited nutrition supply to support the proliferation of many active cancer cells, highlighting the importance of angiogenesis in tumor growth [245]. Different from normal blood vessels with well-organized and functional architecture, tumor vessels are chaotic, irregularly shaped, unorderly distributed, unevenly branched, and tortuous
Conclusions
Tremendous advancements have been made in biomedical imaging, providing valuable tools for the noninvasive visualization of biological events in cancer to better understand cancer biology. This will facilitate the design of more effective cancer diagnostics and therapeutics. Recent advances in cancer biology have shown that the TME plays a critical role in cancer initiation, progression, metastasis, recurrence, and resistance to therapy, and therefore highlights the importance of developing new
Acknowledgements
This research was supported in part by the NIH grant R01 CA194518 and the Fundamental Research Funds for the Central Universities (No. 2016QNA4024).
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This review is part of the Advanced Drug Delivery Reviews theme issue on “Molecular Imaging”.