Imaging the Warburg effect with 23Na MRI and 82Rb positron emission tomography

人们普遍认为，肿瘤或心肌中的缺氧与不发达或阻塞的血管，诱导从有氧呼吸转换为无氧糖酵解作为ATP生产的主要燃料。即使在氧气存在下，肿瘤也显示出对糖酵解的偏好超过氧化代谢。这一观察结果首先由瓦尔堡描述，此后被认为是癌症的标志之一。这种开关背后的糖酵解酶的表达和/或活性受几种细胞信号传导途径控制，这导致糖酵解和乳酸排泄上调，丙酮酸进入TCA循环下调。开发这些途径的抑制剂对于分子靶向的癌症治疗和开发临床上可转化的分子成像方法以报告体内这些过程具有巨大的当前兴趣。Na/K ATP酶（EC 3.6.1.37）是膜转运蛋白，其负责为转化的每个ATP分子泵出3 Na和将2K泵入细胞，其是ATP的主要消耗者。Na/K ATP酶的ATP供应被认为优先来自糖酵解，因为它与糖酵解酶丙酮酸激酶、磷酸甘油酸激酶和甘油醛3-磷酸脱氢酶在空间上共定位。此外，在不具有线粒体的人红细胞中，在用Na离子载体莫能菌素处理后使用葡萄糖消耗的13 C通量分析的先前工作表明，每消耗一分子葡萄糖，6个Na离子被泵出细胞，这表明糖酵解通量和Na/K ATP酶活性之间的紧密耦合，而在一系列癌细胞中的研究表明，用短杆菌肽激活Na/K泵（或用哇巴因抑制）分别导致糖酵解的增加（或减少）。在这种情况下，有证据表明Na/K ATP酶可能是癌症治疗的靶点。接受强心苷如地高辛的乳腺癌患者显示出不同的肿瘤细胞形态，诊断时肿瘤体积较小，随访两年后转移减少，乳房切除术后5年复发率降低。这些观察结果背后的机制尚不清楚，但有新的证据表明，Na/K ATP酶，这是这些糖苷的主要抑制靶点，可能是癌症治疗的治疗靶点。Na/K ATP酶活性和病理学尚未得到很好的理解，并且目前没有Na/K ATP酶的非侵入性临床验证的成像工具。癌症或心脏中的K ATP酶活性。此外，尽管我们的理解有了重大进展，但对瓦尔堡效应的机制仍然知之甚少，成像技术仍然主要依赖于18 FDG PET，其报告葡萄糖转运而不是下游生物能量学。在这个CDT项目中，我们建议开发一种结合体内成像技术，采用23 Na MRI探测细胞内和细胞外钠离子浓度，结合82 Rb PET探测肿瘤和心脏中的Na/K ATP酶活性，以提供一个迄今为止尚未探索的体内代谢失调的窗口。

It is widely accepted that hypoxia in tumours or myocardium with underdeveloped or obstructed vasculature, induces a switch from aerobic respiration to anaerobic glycolysis as the main fuel for ATP production. Tumours display a preference for glycolysis over oxidative metabolism even in the presence of oxygen. This observation was first described by Warburg and has since been recognized as one of the hallmarks of cancer. The expression and/or activity of glycolytic enzymes underlying this switch are controlled by several cell signalling pathways that results in upregulated glycolysis and lactate excretion and downregulated pyruvate entry into the TCA cycle. Developing inhibitors of these pathways is of enormous current interest for molecularly targeted cancer therapeutics and for developing clinically translatable molecular imaging approaches to report on these processes in vivo.Na/K ATPase (EC 3.6.1.37) is the membrane transporter responsible for pumping 3Na out and 2K into the cell for every molecule of ATP converted, of which it is a major consumer. The ATP supply for Na/K ATPase has been suggested to be preferentially derived from glycolysis since it is spatially co-localised with the glycolytic enzymes pyruvate kinase, phosphoglycerate kinase and glyceraldehyde 3-phosphate dehydrogenase. Furthermore, in the human erythrocyte, which possess no mitochondria, previous work using 13C flux analysis of glucose consumption following treatment with the Na ionophore monensin showed that 6 ions of Na are pumped out of the cell per molecule of glucose consumed, suggesting a tight coupling between glycolytic flux and Na/K ATPase activity, while studies in a range of cancer cells have shown that activation of the Na/K pump with gramicidin (or inhibition with ouabain), leads to an increase (or decrease) in glycolysis, respectively. In this context there is evidence that Na/K ATPase could be a target for cancer therapy. Breast cancer patients receiving cardiac glycosides such as digoxin show distinct tumour cell morphologies, smaller tumour volumes at diagnosis, reduced metastasis after two years follow-up and showed reduced recurrence rate five years after mastectomy. The mechanisms underlying these observations are unclear, but there is emerging evidence that Na/K ATPase, which is the principal inhibitory target for these glycosides, could be a therapeutic target for cancer treatment.The relationship between altered metabolism during tumorigenesis, Na/K ATPase activity and pathology is not well understood and there are currently no non-invasive clinically validated imaging tools of Na/K ATPase activity in cancer or the heart. Furthermore despite significant advances in our understanding, the mechanisms underlying the Warburg effect remain poorly understood and imaging techniques still largely rely on 18FDG PET which reports on glucose transport and not downstream bioenergetics. In this CDT project we propose to develop a combination of in vivo imaging techniques employing 23Na MRI for probing intracellular and extracellular sodium ion concentration in combination with 82Rb PET for probing Na/K ATPase activity in tumours and in the heart to offer a hitherto unexplored window on dysregulated metabolism in vivo.