Authors: Ingrid Dijkgraaf Otto C Boerman
Publish Date: 2010/07/09
Volume: 37, Issue: 1, Pages: 104-113
Abstract
Singlephoton emission computed tomography SPECT and position emission tomography PET are the two main imaging modalities in nuclear medicine SPECT imaging is more widely available than PET imaging and the radionuclides used for SPECT are easier to prepare and usually have a longer halflife than those used for PET In addition SPECT is a less expensive technique than PET Commonly used gamma emitters are 99mTc Emax 141 keV T 1/2 602 h 123I Emax 529 keV T 1/2 130 h and 111In Emax 245 keV T 1/2 672 h Compared to clinical SPECT PET has a higher spatial resolution and the possibility to more accurately estimate the in vivo concentration of a tracer In preclinical imaging the situation is quite different The resolution of microSPECT cameras 05 mm is higher than that of microPET cameras 15 mm In this report studies on new radiolabelled tracers for SPECT imaging of angiogenesis in tumours are reviewedAngiogenesis the formation of new blood vessels from preexisting vasculature is one of the key requirements if solid tumours are to grow beyond 2–3 mm3 since diffusion is no longer sufficient to supply the tissue with oxygen and nutrients 1 Tumourinduced angiogenesis is a complex multistep process that follows a characteristic cascade of events mediated and controlled by growth factors cellular receptors and adhesion molecules 2 3 4 In this process five phases can be distinguished 1 endothelial cell activation 2 basement membrane degradation 3 endothelial cell migration 4 vessel formation and 5 angiogenic remodelling 5The activation of preexisting quiescent vessels can be triggered by hypoxia Hypoxia induces the expression of hypoxiainducible factor HIF which binds to the hypoxic response element As a result the expression of hypoxiainducible genes such as vascular endothelial growth factor VEGF carbonic anhydrase IX CAIX plateletderived growth factor PDGF and transforming growth factorα TGFα is induced 6Activated endothelial cells express the dimeric transmembrane integrin αvβ3 which interacts with extracellular matrix proteins vitronectin tenascin fibronectin ao and regulates migration of the endothelial cell through the extracellular matrix during vessel formation 7 8 The activated endothelial cells synthesize proteolytic enzymes such as matrix metalloproteinases MMPs used to degrade the basement membrane and the extracellular matrix 9 Initially endothelial cells assemble as solid cords Subsequently the inner layer of endothelial cells undergoes apoptosis leading to the formation of the vessel lumen Finally this primary immature vasculature undergoes extensive remodelling during which the vessels are stabilized by pericytes and smooth muscle cells This step is often incomplete in tumours resulting in the characteristic increased permeability of tumour vesselsBased on a balance between proangiogenic and antiangiogenic factors a tumour can stay dormant for a very long time period until the socalled angiogenic switch occurs In most tissues tumours can only grow to a lifethreatening size if the tumour is able to trigger angiogenesis In tissues with high vessel densities eg liver brain ao tumours may also progress via angiogenesisindependent cooption of the preexistent vasculature 10In summary tumourinduced angiogenesis is a multistep process and a key feature of a tumour lesion that has major impact on the biological behaviour of the lesion Inhibition of angiogenesis is a new cancer treatment strategy that is now being widely investigated clinically Researchers have begun to search for objective measures that indicate pharmacological responses to antiangiogenic drugs Therefore there is great interest in techniques to visualize angiogenesis in growing tumours noninvasively During the past decade several markers of angiogenesis have been identified and specific tracers targeting these markers have been developedVEGF is a key regulator of angiogenesis during embryogenesis skeletal growth and reproductive functions The expression of VEGF is upregulated by environmental stress caused by hypoxia anaemia myocardial ischaemia and tumour progression to initiate neovascularization 11 Via alternative mRNA splicing the human VEGFA gene gives rise to four isoforms having 121 165 189 and 206 amino acids VEGF121 VEGF165 VEGF189 and VEGF206 respectively 12 13 Less frequent splice variants have been identified more recently including VEGF145 14 VEGF183 15 VEGF162 16 and VEGF165b 17 The VEGF isoforms differ not only in their molecular mass but also in their solubility and receptorbinding characteristicsInitially VEGF receptors were identified on the cell surface of vascular endothelial cells in vitro 18 19 and in vivo 20 21 Subsequently it was demonstrated that receptors for VEGF also are expressed on bone marrowderived cells such as monocytes 22 VEGFA binds two related receptor tyrosine kinases RTKs VEGFR1 and VEGFR2 Both receptors consist of seven Iglike domains in the extracellular domain a single transmembrane region and a consensus tyrosine kinase sequence that is interrupted by a kinase insert domain 23 24 25 VEGFR1 binds VEGF with a higher affinity compared to VEGFR2 Kd 25 vs 75–250 pM 26 27 28 VEGFR1 is considered to be a decoy receptor and VEGFA only signals through VEGFR2 29
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