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Challenges for imaging angiogenesis

¹The Paul Strickland Scanner Centre, Mount Vernon Hospital, Northwood, Middlesex HA6 2RN, UK and ²Department of Biological Regulation, The Weizmann Institute of Science, Rehovot 76100, Israel

Angiogenesis, the sprouting of new capillaries from existing blood vessels, and vasculogenesis, the de novo generation of blood vessels, are the two primary methods of vascular expansion by which nutrient supply to tissues is adjusted to match physiological demand. Accordingly, vasculogenesis is an integral and essential component of embryonic development, and angiogenesis accompanies organ growth and regeneration [1]. Angiogenesis also occurs during wound repair, in spontaneous growth of collateral vessels in response to ischaemia, in the ovaries and uterus during the female reproductive cycle, in retinopathy and in cancer. The angiogenic process is a complex multistep phenomenon involving many growth factors and interactions between a number of cell types [2]. Angiogenesis is invoked by expression of pro-angiogenic growth factors in cells of the target tissue and by suppression of anti-angiogenic factors. Expression of angiogenic growth factors can be induced as a response to hypoxic stress, by hormonal stimulation, but can also result from activation of oncogenes. Normal vessels activated by vascular endothelial growth factor (VEGF) respond within minutes by dilation and increased permeability to macromolecular serum proteins. Extravasation of plasma proteins leads to deposition of a provisional extracellular matrix (ECM), which facilitates endothelial cell migration. Prior to endothelial proliferation and migration, activated vessels show local shedding of pericytes and smooth muscle cells. These perivascular cells are essential for maintaining vascular integrity but also further suppress endothelial cell proliferation. Proliferation, migration and elongation of endothelial capillaries require degradation of the ECM, and endothelial cells thus activated release a number of proteolytic enzymes, including collagenase. Tumours may benefit from the ECM remodelling and growth factors released during the early stages of angiogenesis, even in the absence of increased perfusion [3]. This process leads to the generation of a functional but immature endothelial plexus. The final stages of angiogenesis include stabilization, remodelling and maturation of the new vessels by recruitment of pericytes and smooth muscle cells.

Biological and clinical importance of tumour angiogenesis

Tumour growth beyond a millimetre in solid tissues cannot occur without vascular support [4]. Transgenic animal tumour model experiments have shown that progression from an in situ to an invasive cancer is accompanied by the onset of angiogenesis [5]. There are a number of clinical examples where vascularization has been related to tumour progression, for example in the change from breast ductal carcinoma in situ to invasive cancer [6, 7]. Immunohistochemical techniques show changes consistent with this observation; for example, expression of the endothelial cell-specific tyrosine kinase receptor Tie-2 (TEK) is increased during the transition from benign to invasive cancer [8]. Patient prognosis is related to angiogenesis; elevated tumour levels of VEGF are associated with poorer overall prognosis in breast cancer [9–11]. Immunohistochemical staining measurement of angiogenic activity, known as microvessel density (MVD), is an important prognostic factor for overall survival that is independent of other known prognostic variables, including stage, grade and lymph node status in a number of cancer types [12]. In addition, vascular access is essential for a tumour to be able to metastasize to distant sites [5].

Manipulation of angiogenesis

Therapeutic manipulation of angiogenesis follows two main avenues. (1) Inducing angiogenesis would be beneficial in the treatment of ischaemic vascular disease [13, 14]. In these cases the aim is to improve tissue perfusion and it is therefore necessary to ensure prolonged stability of the generated neovasculature. (2) In cancer patients the aim is to irreversibly (or chronically) suppress tumour progression by inhibition of further vascular expansion. Pharmacological targeting of tumour blood vessels may be achieved by three major mechanisms: (1) true angiogenesis inhibition; (2) vascular targeting; and (3) non-selective anti-angiogenic effects. True angiogenesis inhibitors are designed to halt vascular sprouting and do not destroy pre-existing tumour blood vessels. In animal tumour studies, true angiogenesis inhibitors generally slow tumour growth over days to weeks. Clinical studies using angiogenesis inhibitors generally show that disease stabilization occurs, although individual patients may achieve partial or complete response [15, 16]. Vascular targeting agents destroy pre-existing tumour vasculature. The effect of these agents is seen within hours in animal and human studies [17, 18]. Acute endothelial cell death, intravascular thrombosis and tumour hypoxia result in necrosis. Clinically, vascular targeting agents cause tumour pain within hours of drug administration. Non-selective anti-angiogenic agents exert anti-proliferative or cytotoxic effects on multiple cell types, including endothelial cells. Adjustment of drug dose, schedule or delivery mode may produce marked anti-endothelial effects. Several conventional chemotherapeutic drugs have anti-angiogenic effects when administered at doses below the maximum tolerated dose [19].

Imaging angiogenic targeted treatments

An understanding of the dynamics of angiogenesis cannot be achieved without an integrated analysis of morphological, functional and molecular approaches, which shed light on changes in tissues. Imaging tools are important for understanding the pathways regulating angiogenesis, and determining the timing and microenvironmental controls of gene expression. Imaging techniques can also analyse angiogenic responses to specific perturbations of the angiogenic process, either by overexpression or null mutations of specific genes, or with the use of specific inhibitors that target known signalling pathways.

Functional characterization of the tumour neovasculature by imaging will be important for the treatment of patients receiving anti-angiogenic therapy. Clinical imaging of angiogenesis should be designed to address the following aims.

1. Selection of the optimal treatment. The number of anti-angiogenic compounds entering clinical trials is rapidly increasing, and many additional compounds are at various stages of development, each targeting a different point in the process. The efficacy of treatment could vary between tumours, and thus the choice of optimal treatment will require information on the biology and functional status of the tumour vasculature. Characterization of the angiogenic status of the specific tumour may therefore allow rational selection of patients to specific treatments.
   
2. Tailored dose optimization. Clinical trials of anti-angiogenic treatments have reported very low toxicity compared with chemotherapy. Toxicity-based selection of dose may therefore not be optimal for in vivo activity. Imaging may aid in dose selection if it were possible to show quantitative biological effects specified by a mechanism-based knowledge of drug action.
   
3. Detection of early anti-angiogenic response. The intrinsic redundancy of signalling mechanisms associated with angiogenesis will lead to partial or complete resistance of the tumour vessels to therapy. Interest in imaging techniques that can provide early indicators of effectiveness at a functional or molecular level has therefore increased. Tumour response to treatment can be detected by functional imaging techniques that are capable of monitoring changes such as perfusion, blood volume or microvessel permeability.
   
4. Analysis of the impact of treatment on tumour progression. Monitoring the therapeutic effects of anti-angiogenic therapy is expected to be harder to detect and quantify. This is because anti-angiogenic treatments may not result in substantial reductions in tumour volume, and conventional size measurements of response may be insensitive or markedly delayed even when there is a significant anti-vascular effect. Imaging-based approaches will also be valuable for monitoring chronic anti-angiogenic treatment, as these therapies will be used for long-term stabilization of cancer. As anti-angiogenic therapy is envisaged as requiring long-term treatment, non-invasive and cost effective techniques would be highly desirable.
   

Conventional imaging techniques will remain important tools, since tumour size monitoring will remain an important response variable. These techniques have also been developed to quantify functional characteristics associated with tissue vascularity. CT can be performed with contrast medium to measure vascular characteristics including blood flow, blood volume, mean fluid transit time and capillary permeability [20]. Functional CT can show increases in tissue perfusion that may reflect underlying malignancy, even when there is no gross anatomical abnormality present [21]. However, there has so far been little validation of functional CT with accepted surrogates of angiogenesis; poor anatomical coverage, increased sensitivity to physiological motion and radiation remain potential drawbacks. Ultrasound imaging can identify vascular features in tumours at different levels of resolution (40–200 µm diameter vessels), depending upon the technique employed [22]. Contrast enhanced ultrasound using an intravascular agent can generate indices of blood flow, blood volume or vascularity within malignant tissues. Targeted imaging using ultrasound destruction of microbubbles can visualize vessels at high resolution within the tumour vascular tree [23]. To date, however, there has been little validation of ultrasound with accepted surrogates of angiogenesis; poor accessibility to certain anatomical regions and operator dependence are outstanding issues that remain to be resolved. MRI can measure both blood volume and blood vessel permeability using dynamic enhancement with extracellular or blood pool contrast agents. Contrast enhanced MRI can distinguish between normal and malignant tissues, reflecting the hyperpermeable tumour vasculature [24]. Contrast uptake correlates with microvessel density in human and animal experimental tumours [24, 25]. Administration of anti-VEGF monoclonal antibodies in experimental breast cancers in mice produces reductions in vascular permeability that are detectable by MRI [26]. Tumour angiogenesis can also be analysed using intrinsic blood and oxygenation level dependent (BOLD) contrast MRI for mapping mature and immature vessels and their differential sensitivity to perturbations in VEGF expression [27]. Using radiotracers, such as ¹⁸FDG, ¹⁵H₂O and ¹¹CO, positron emission tomography (PET) can accurately quantify tumour functional characteristics such as glucose metabolism, blood flow and volume [28]. PET remains an expensive imaging modality because of the use of short-lived isotopes that require cyclotron production and radiochemistry facilities on-site.

Specific molecular markers on newly formed vessels can be imaged by novel imaging techniques. Many of these markers have also been identified as potential targets of vascular-directed therapies. Specific examples of these kinds of imaging techniques include imaging of alphaVbeta3 endothelial integrins by paramagnetic liposomes [29]. These paramagnetic liposomes can be designed to carry anti-angiogenic or cytotoxic drugs, thus enabling both treatment and visualization of angiogenic endothelium in tumours. Other approaches include targeting of angiogenesis-associated fibronectin isoforms using optical probes [30] and imaging labelled antibodies targeting tumour growth factor ß receptor [31]. A number of anti-angiogenic agents also cause endothelial and tumour cell apoptosis. Apoptosis is a physiological form of programmed cell death, which is critical for organ development, tissue homeostasis and the removal of defective cells. Defects in the apoptotic pathway are a key feature of cancer. Markers of endothelial cell apoptosis, such as annexin V, may be adapted for radiolabelling, thus enabling direct visualization of sites where there is anti-angiogenic and anti-tumour drug action [32].

Challenges for currently available imaging investigations

From the above discussion it is clear that there are a variety of imaging techniques that can evaluate microvascular structure and function. This variety can make it difficult to make meaningful comparisons between different tissue types and to compare data obtained from different imaging centres. The clinical imaging community needs to agree on a limited number of examination and analysis protocols to enable techniques to be validated and used in clinical trials. Another issue that needs to be addressed is that of data collection in body parts where there is a large degree of physiological movement such as the lungs and liver. For PET, CT and MRI, the presence of motion can invalidate functional vascular parameter estimates. The quantitative potential of imaging techniques is attractive when monitoring the effects of physical and pharmaceutical treatments. Quantification techniques aim to minimize errors that can result from the use of different equipment and imaging protocols. Tumour perfusion is typically quantified by fitting a kinetic model to measured imaging data from which parameter estimates are derived. Such models are based on some understanding of physiological processes and can provide insights into tumour biology. We do not have models that fit all data, and more sophisticated models that provide insights into tissue compartment behaviour are needed. Measurement error is the variation between measurements of the same quantity on the same individual. An estimate of measurement error enables us to decide whether a change in observation represents a real change. Data addressing the precision and measurement variability of different imaging techniques are urgently needed and should be an integral part of any new prospective study evaluating angiogenic response to therapy. Some PET data exist and a limited amount of data are available for CT and MRI. Any imaging assay of tumour microvascular characteristics must be rigorously validated against accepted surrogates of angiogenesis. Unfortunately, no single imaging assay or surrogate may be adequate to reflect the whole spectrum of events involved in angiogenesis. Commonly used and appropriate surrogates include histological MVD, as counted on factor VIII or CD34-stained tumour specimens, and vascular maturation index (VMI) [33]. Quantitative measures of VEGF or other known mediators of angiogenesis, in the tumour tissue itself or in the plasma, can also be compared with the imaging assay results. Similarly, the imaging assays need to be tested against each other to determine their relative utility. Analysis and presentation of imaging data needs to take into account the heterogeneity of tumour vascular characteristics. The regional variability observed on imaging probably reflects variation in microvessel density, VEGF expression, areas of fibrosis, avascularity and necrosis. Pixel mapping techniques with histogram analysis are examples of methods by which such heterogeneity can be displayed and quantified.

Conclusions

There is a definite clinical need to develop non-invasive imaging assays of tumour angiogenesis. Such imaging techniques will have a central role in the evaluation of novel anti-angiogenic and pro-angiogenic therapies. In addition to PET, conventional techniques (CT, MRI, ultrasound) ordinarily used to document tumour size may be adapted to measure vascular parameters such as blood flow, blood volume, permeability, microvessel density and tumour metabolism. There are a number of requirements that need to be met before these and other techniques can become diagnostic tools for characterizing microvasculature. Requirements include agreed protocols for data acquisition, analysis and presentation methods. Appropriate image processing and visualization tools will be needed to achieve this. Imaging techniques need to be able to sample the whole tumour volume, particularly if the technique is to extend to organs with significant physiological motion. Future approaches for imaging angiogenesis will involve imaging the molecular features of new blood vessel growth. Novel imaging targets include cell surface integrins, endothelial apoptosis, angiopoietins and the infrared signature of angiogenesis. Given the lead-time between the development of a new therapeutic approach or drug in the laboratory and its evaluation in the clinic, researchers need to fully evaluate currently available and new methods for characterizing tumour microvascular function. Imaging angiogenic responses, optimized trial designs and more potent anti-angiogenic agents will be needed to bring anti-angiogenic cancer therapy into standard oncology practice.

Footnotes

This Commentary is linked to the BIR Scientific Meeting "Imaging for the assessment of angiogenesis in cancer treatment", organized by the British Institute of Radiology Diagnostic Methods Committee, to be held at The British Institute of Radiology on 14 December 2001. To register for this meeting, or for further information, please contact Isabel Hinings at the BIR (tel. +44 (0)20 7307 1417).

Received for publication June 18, 2001. Accepted for publication July 5, 2001.

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This Article Full Text (PDF) Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Padhani, A R Articles by Neeman, M Search for Related Content PubMed PubMed Citation Articles by Padhani, A R Articles by Neeman, M