Vessel calibre—a potential MRI biomarker of tumour response in clinical trials
Nature Reviews Clinical Oncology
Our understanding of the importance of blood vessels and angiogenesis in cancer has increased considerably over the past decades, and the assessment of tumour vessel calibre and structure has become increasingly important for in vivo monitoring of therapeutic response. The preferred method for in vivo imaging of most solid cancers is MRI, and the concept of vessel-calibre MRI has evolved since its initial inception in the early 1990s. Almost a quarter of a century later, unlike traditional
... ast-enhanced MRI techniques, vessel-calibre MRI remains widely inaccessible to the general clinical community. The narrow availability of the technique is, in part, attributable to limited awareness and a lack of imaging standardization. Thus, the role of vessel-calibre MRI in early phase clinical trials remains to be determined. By contrast, regulatory approvals of antiangiogenic agents that are not directly cytotoxic have created an urgent need for clinical trials incorporating advanced imaging analyses, going beyond traditional assessments of tumour volume. To this end, we review the field of vessel-calibre MRI and summarize the emerging evidence supporting the use of this technique to monitor response to anticancer therapy. We also discuss the potential use of this biomarker assessment in clinical imaging trials and highlight relevant avenues for future research. blood vessels independent of existing vessels, either comprising endothelial cells (vasculogenesis) or tumour cells in the absence of endothelial cells and fibroblasts (vascular mimicry); and transdifferentiation of tumour cells into endothelial cells. 5 Initially, many tumours grow by vessel co-option; however, at some point an angiogenic switch occurs that leads to overproduction of proangiogenic factors, such as vascular endothelial growth factor (VEGF), fibroblast growth factors (FGFs), angiopoietin-2 (ANG-2) and chemokines, which in turn leads to new vessel formation and vessel maturation ( Figure 1) . 1, 5, 17 The new vessels are predominantly immature and abnormal (overdilated, hyperpermeable, tortuous and disrupted), resulting in variable perfusion; 2,7 some tumour tissues receive too much blood, whereas others do not receive enough and are, therefore, starved of oxygen and nutrients. 2, 7 In parallel, solid stress imparted by proliferating cancer cells, stromal cells and the extracellular matrix can lead to compression of vessels, reducing blood flow ( Figure 1) . 3, 4, 20, 21 Consequently, the tumour vascular bed is spatially and temporally heterogeneous with regard to multiple vessel parameters, not least vessel calibre, which creates an irregular microenvironment that adversely affects drug delivery and introduces variation in cellular responses to therapeutic agents, resulting in decreased efficacy of cancer therapy. 8 Indeed, this microenvironment is characterized by hypoxia (low oxygen concentration), 22,23 low pH, increased solid stress 4,20 and high interstitial fluid pressure 24 -factors that can all contribute to tumour progression and resistance to various treatments (such as radiotherapy, chemotherapy and immunotherapy). 8,21 Cancer therapies that affect vessel calibres Treatments for cancer not only affect cancer cells, but also have broader effects on the tumour microenvironment, including the vasculature. Following radiation treatment, oxygen-deprived tumour tissue might become reoxygenated owing to radiation-induced death of surrounding radiosensitive and oxygen-rich cell populations that were previously obstructing nearby tumour blood vessels. 5 This alteration in the microvascular environment could potentially lead to decompression of tumour vessels, increased vessel calibres and increased perfusion of tumour tissues. 23 In addition, some chemotherapeutic drugs might kill proliferating endothelial cells and, therefore, act as antiangiogenic agents, 17 with the possible consequence of modifying blood-vessel calibres. Clearly, distinguishing treatmentrelated changes in tumour-vessel calibres from the alterations induced by tumour growth is important for patient management and clinical trial design. Blocking angiogenesis was initially proposed as a strategy to starve tumours of blood flow and halt the delivery of nutrients required for cell survival, growth and proliferation. 25 However, the therapeutic potential of antiangiogenic agents also seems to be attributable to mechanisms other than simple destruction and 'pruning' of the tumour vasculature; 8 Jain and colleagues 1,26,27 have proposed that antiangiogenic agents can transiently normalize the tumour vasculature, converting the heterogeneous, abnormally dilated and hyperpermeable vessels to a more-efficient state that results in improved blood perfusion and decreased vessel diameters. This effect might create a window of opportunity during which various concomitantly administered therapies (radiation, chemotherapy or immunotherapy, for example) are likely to be most effective. 27,28 Additionally, antiangiogenic therapy could potentially disrupt the vascular cancer-stem-cell niche. 17 Probably, a range of mechanisms Emblem et al.