PET imaging of integrins
All cells (excluding blood cells) adhere to the surrounding extracellular matrix (ECM) by membrane receptors, mainly integrins. Integrins are heterodimeric proteins, consisting of α and β subunits, which have a large extracellular domain, a single transmembrane domain, and short intracellular tail. The specificity of the integrin is determined by the combination of the α and β subunits. Fibronectin and several other ECM proteins expose short peptide loops, such as Arg-Gly-Asp (RGD) sequence, which is a common ligand for many integrins. Endothelial cells express endoglin, which also contains the RGD motif. The cytoplasmic tail of integrins are connected to the cells cytoskeleton. Binding to and separation from their cytoplasmic signalling molecules, cytoskeleton, and ECM ligands are associated via conformational changes. Integrin receptors can signal bidirectionally: intracellular signalling pathways may activate or deactivate the extracellular part via large conformational changes.
Integrins are important in tissue remodelling, cell migration, proliferation, and differentiation. Haemostasis and regulation of blood clotting is largely based on integrins. Integrins mediate the entry of lymphocytes into inflamed tissue, and can therefore be targeted in therapy for autoimmune diseases. Integrins expressed by the cells of CNS are important in synaptic plasticity, synapse formation, and regulation of myelination and status of microglia.
Shank-associated RH domain-interacting protein (SHARPIN, alias SIPL1) is a cytosolic protein that controls integrin-dependent cell adhesion and migration in several normal and malignant cell types, and loss of SHARPIN correlates with increased integrin activity in mice (Siitonen et al., 2019).
Integrin αvβ3 is a cell membrane glycoprotein receptor (“vitronectin receptor”) that interacts with specific ligands in extracellular matrix (ECM), playing a key role in angiogenesis, inflammation, fibrosis, osteoporosis, and tumour metastasis formation. Expression of αvβ3 integrin is increased in activated endothelial cells and tumour cells, but is low in most normal tissues.
Extracellular (interstitial) matrix proteins, such as vitronectin, fibronectin, and thrombospondin) contain a Arg-Gly-Asp (RGD) tripeptide sequence, which binds to many integrins, including αvβ3. Radiolabelled peptides containing the RGD peptide can be used to detect the increased expression of αvβ3 integrin in tumours and infarcted myocardium. Multimerization of RGD-domains increases the affinity and specific uptake of the tracer (Dijkgraaf et al., 2011).
PET imaging of integrin αvβ3 is already an important tool for tumour diagnosis and treatment monitoring (Chen et al., 2016). [68Ga]-DOTA-E-[c(RGDfK)]2 is one of the proposed PET tracers for αvβ3 imaging.
Increased integrin αvβ3 expression is also a potential biomarker of successful tissue repair processes. After myocardial infarction, its expression is upregulated during angiogenesis. In rat model of myocardial infarction, increased uptake of [18F]galacto-RGD in the defect area predicted better healing (Sherif et al., 2012). Similar results have been obtained in patients with myocardial infarction using [18F]fluciclatide ([18F]AH111585) (Jenkins et al., 2017).
Integrin αvβ5 has a role in regulation of the integrity of endothelial barrier; VEGF-induced vascular leakage is diminished when αvβ5 inactivated. Integrin αvβ5 is expressed on endothelial and epithelial cells, and fibroblasts. Blocking αvβ5 reduces ischemia-reperfusion damage in rat model of acute kidney injury (McCurley et al., 2017).
[68Ga]DOTA-RGD binds to both αvβ3 and αvβ5 integrins (Haukkala et al., 2009).
Epithelial integrin αvβ6 is expressed by many carcinoma cell types, providing a target for radionuclide therapy and imaging (Färber et al., 2018).
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Updated at: 2019-03-11
Created at: 2017-03-05
Written by: Vesa Oikonen