The Warburg Effect Is Associated With Tumor Aggressiveness in Testicular Germ Cell Tumors
The Warburg Effect Is Associated With Tumor Aggressiveness in Testicular Germ Cell Tumors
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DOI：
10.3389/fendo.2019.00417
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发表时间：
2019-06-28
影响因子：
5.2
通讯作者：
Pinheiro, Celine
中科院分区：
文献类型：
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作者：
Bonatelli, Murilo;Silva, Eduardo C. A.;Pinheiro, Celine
睾丸生殖细胞肿瘤(TGCT)是一种罕见的肿瘤，是发生在年轻男性的最常见的实体恶性肿瘤。尽管这些肿瘤对以铂为基础的化疗有很好的反应，但一些患者对治疗无效，临床结果很差。在癌症发生和肿瘤发展期间，癌细胞将能量代谢重新编程为高糖酵解表型，这是癌症的一个新标志。这种现象被称为Warburg效应或有氧糖酵解，涉及代谢相关蛋白的过度表达，如葡萄糖和单羧酸转运体、pH调节器和细胞内糖酵解酶。TGCT的代谢谱很少被研究，最近，这种癌细胞的代谢重排与这些肿瘤的侵袭性临床病理特征有关。单羧酸转运体4(MCT4)在TGCT中的过度表达被认为是一个预后不良的因素，也是一个有希望的治疗靶点。因此，本研究的主要目的是评估TGCT中关键代谢相关蛋白的预后价值。应用免疫组织化学方法检测148例成年男性TGCTs中CD44、葡萄糖转运蛋白1(GLUT1)、碳酸氢酶IX(CAIX)、己糖激酶II(HKII)和乳酸脱氢酶V(LDHV)的表达及其与临床病理参数的关系。此外，还对配对的正常组织进行了评估。样本包括75例精原细胞瘤和73例非精原细胞瘤。与配对的正常组织相比，恶性组织中Glut1和CD44的表达显著增加。相反，HKII和LDHV在恶性标本中的表达显著降低。在临床病理方面，CAIX的表达与疾病复发显著相关，而HKII的表达与TGCT的侵袭性特征显著相关，包括高分期和非精原细胞瘤组织学特征。总之，这项研究为TGCT的代谢特征带来了新的见解，显示了与Warburg效应相关的蛋白质表达的变化，以及高糖酵解和耐酸表型与侵袭性临床病理参数的关系。
Testicular Germ Cell Tumors (TGCTs) are a rare group of neoplasms and the most common solid malignancy arising in young male adults. Despite the good response of these tumors to platinum-based chemotherapy, some patients are refractory to treatment and present poor clinical outcomes. During carcinogenesis and tumor development, cancer cells reprogram energy metabolism toward a hyper-glycolytic phenotype, an emerging hallmark of cancer. This phenomenon, known as the Warburg effect or aerobic glycolysis, involves overexpression of metabolism-related proteins, like glucose and monocarboxylate transporters, pH regulators and intracellular glycolytic enzymes. The metabolic profile of TGCTs is very little explored and, recently, this metabolic rewiring of cancer cells has been associated with aggressive clinicopathological characteristics of these tumors. The overexpression of monocarboxylate transporter 4 (MCT4) in TGCTs has been pointed out as a poor prognostic factor, as well as a promising therapeutic target. As a result, the main aim of the present study was to evaluate the prognostic value of key metabolism-related proteins in TGCTs. The immunohistochemical expressions of CD44 (as a monocarboxylate transporter chaperone), glucose transporter 1 (GLUT1), carbonic anhydrase IX (CAIX), hexokinase II (HKII) and lactate dehydrogenase V (LDHV) were evaluated in a series of 148 adult male patients with TGCTs and associated with clinicopathological parameters. In addition, paired normal tissues were also evaluated. The sample included 75 seminoma and 73 non-seminoma tumors. GLUT1 and CD44 expression was significantly increased in malignant samples when compared to paired normal samples. Conversely, HKII and LDHV expressions were significantly decreased in malignant samples. Concerning the clinicopathological values, CAIX expression was significantly associated with disease recurrence, while HKII expression was significantly associated with aggressive characteristics of TGCTs, including higher staging and non-seminoma histology. In conclusion, this study brings new insights on the metabolic characteristics of TGCTs, showing alterations in the expression of proteins related with the Warburg effect, as well as associations of the hyper-glycolytic and acid-resistant phenotype with aggressive clinicopathological parameters.