Ocak Iclal, Baluk Peter, Barrett Tristan, McDonald Donald M, Choyke Peter
Molecular Imaging Program, National Institutes of Health, Bethesda, Maryland 20892-1182, USA.
Front Biosci. 2007 May 1;12:3601-16. doi: 10.2741/2337.
Knowledge of the different physiology and endothelial markers present in tumor vessels is essential to enable both the development of new anti-angiogenic chemotherapeutic agents and of more specific imaging techniques. Tumor blood vessels are disorganized, irregular in caliber, tortuous, and do not have specialized features of normal arterioles, capillaries or venules. Neo-angiogenic tumor vessels have large gaps between or through cells, loose pericytes, and discontinuities or redundant layers within the basement membrane, rendering these vessels hyper-permeable. Furthermore, the endothelia of tumor vessels may express unique markers on their surface. Imaging is becoming increasingly important in the evaluation of angiogenesis. Clinical imaging is minimally invasive and enables sampling of the whole tumor in a nondestructive manner. The patterns of increased permeability seen on Dynamic contrast-enhanced Magnetic Resonance Imaging (DCE-MRI) mirror the known ultrastructural defects associated with angiogenic vessels. Conventional low-molecular weight contrast agents are currently in clinical use for DCE-MRI studies and have proven successful in detecting changes related to novel angiogenic inhibitors. However, they are relatively non-specific. Macromolecular contrast media may be more suitable for imaging tumor vessels. It is hoped that imaging modalities can be adapted to specifically target markers expressed on the endothelium of tumor vessels. The number of cell surface markers of angiogenesis is relatively low, and only small amounts of contrast agents can bind to these receptors; currently only Positron Emission Tomography (PET) and Single Photon Emission Computed Tomography (SPECT) tracers have sufficient sensitivity to allow detection at this low level. Despite limitations in their spatial resolution, PET and SPECT imaging are more likely to enter the clinic as targeted angiogenesis imaging methods. The quest for selective targets on the tumor vasculature continues, currently the integrin family of receptors offer the most promise but other targets are being pursued by investigators. Serial analysis of gene expression or in vivo phage display may help identify new, more selective, markers that can be utilized for the targeted imaging and treatment of angiogenesis.
了解肿瘤血管中存在的不同生理学和内皮标志物对于开发新的抗血管生成化疗药物以及更具特异性的成像技术至关重要。肿瘤血管杂乱无章，管径不规则，蜿蜒曲折，不具备正常小动脉、毛细血管或小静脉的特殊特征。新生血管生成的肿瘤血管在细胞之间或穿过细胞时有大的间隙，周细胞松散，基底膜内有间断或多余的层，使这些血管具有高通透性。此外，肿瘤血管的内皮细胞可能在其表面表达独特的标志物。成像在血管生成评估中变得越来越重要。临床成像具有微创性，能够以非破坏性方式对整个肿瘤进行采样。动态对比增强磁共振成像（DCE-MRI）上看到的通透性增加模式反映了与血管生成血管相关的已知超微结构缺陷。传统的低分子量造影剂目前在DCE-MRI研究中用于临床，已被证明在检测与新型血管生成抑制剂相关的变化方面是成功的。然而，它们相对非特异性。大分子造影剂可能更适合于肿瘤血管成像。希望成像方式能够适应特异性靶向肿瘤血管内皮细胞上表达的标志物。血管生成的细胞表面标志物数量相对较少，只有少量造影剂能够与这些受体结合；目前只有正电子发射断层扫描（PET）和单光子发射计算机断层扫描（SPECT）示踪剂具有足够的灵敏度，能够在如此低的水平上进行检测。尽管PET和SPECT成像在空间分辨率方面存在局限性，但它们作为靶向血管生成成像方法更有可能进入临床。对肿瘤脉管系统上选择性靶点的探索仍在继续，目前整合素受体家族最有前景，但研究人员也在寻找其他靶点。基因表达的系列分析或体内噬菌体展示可能有助于识别可用于血管生成靶向成像和治疗的新的、更具选择性的标志物。
