瓦尔堡效应作为膀胱癌的治疗靶点以及相关分子靶点的肿瘤内异质性,Cancer Science

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瓦尔堡效应作为膀胱癌的治疗靶点以及相关分子靶点的肿瘤内异质性
Cancer Science ( IF 4.5 ) Pub Date : 2021-06-28 , DOI: 10.1111/cas.15047
Julie E Burns ₁ , Carolyn D Hurst ₁ , Margaret A Knowles ₁ , Roger M Phillips ₂ , Simon J Allison _{1,

2}

Affiliation

膀胱癌是全球第十大常见癌症。对于肌层浸润性膀胱癌（MIBC），治疗包括根治性膀胱切除术、放疗和化疗；然而，结果普遍不佳。对于非肌层浸润性膀胱癌（NMIBC），肿瘤复发很常见。迫切需要更有效且危害更小的治疗方法。在此，研究了不同阶段和级别的膀胱癌细胞以及在新鲜切除的临床组织中膀胱癌细胞代谢重编程依赖于有氧糖酵解（瓦尔堡效应）和相关分子治疗靶点的表达。重要的是，分析表明 Warburg 效应是 NMIBC 和 MIBC 的一个特征。在两种体外诱导上皮间质转化 (EMT) 膀胱癌模型中，EMT 刺激与乳酸产生增加相关，乳酸是有氧糖酵解的最终产物。大多数膀胱癌细胞系中促进丙酮酸酶促还原为乳酸的乳酸脱氢酶 A (LDH-A) 的蛋白质水平较高（与催化逆反应的 LDH-B 相比），但其水平与有氧糖酵解率。虽然 LDH-A 在正常尿路上皮细胞中表达，但通过 RNAi 敲低 LDH-A 可选择性诱导尿路上皮癌细胞凋亡，而正常细胞不受影响，这表明 LDH-A 是膀胱癌的癌症选择性治疗靶点。LDH-A 和其他潜在治疗靶点（MCT4 和 GLUT1）在患者临床标本中表达；然而，阳性染色在切片的不同区域以及与血管的距离不同而变化。这种肿瘤内异质性具有重要的治疗意义，并表明肿瘤细胞代谢耦合的可能性。

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The Warburg effect as a therapeutic target for bladder cancers and intratumoral heterogeneity in associated molecular targets

Bladder cancer is the 10th most common cancer worldwide. For muscle-invasive bladder cancer (MIBC), treatment includes radical cystectomy, radiotherapy, and chemotherapy; however, the outcome is generally poor. For non–muscle-invasive bladder cancer (NMIBC), tumor recurrence is common. There is an urgent need for more effective and less harmful therapeutic approaches. Here, bladder cancer cell metabolic reprogramming to rely on aerobic glycolysis (the Warburg effect) and expression of associated molecular therapeutic targets by bladder cancer cells of different stages and grades, and in freshly resected clinical tissue, is investigated. Importantly, analyses indicate that the Warburg effect is a feature of both NMIBCs and MIBCs. In two in vitro inducible epithelial-mesenchymal transition (EMT) bladder cancer models, EMT stimulation correlated with increased lactate production, the end product of aerobic glycolysis. Protein levels of lactate dehydrogenase A (LDH-A), which promotes pyruvate enzymatic reduction to lactate, were higher in most bladder cancer cell lines (compared with LDH-B, which catalyzes the reverse reaction), but the levels did not closely correlate with aerobic glycolysis rates. Although LDH-A is expressed in normal urothelial cells, LDH-A knockdown by RNAi selectively induced urothelial cancer cell apoptotic death, whereas normal cells were unaffected—identifying LDH-A as a cancer-selective therapeutic target for bladder cancers. LDH-A and other potential therapeutic targets (MCT4 and GLUT1) were expressed in patient clinical specimens; however, positive staining varied in different areas of sections and with distance from a blood vessel. This intratumoral heterogeneity has important therapeutic implications and indicates the possibility of tumor cell metabolic coupling.

更新日期：2021-09-01

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