Bonatelli Murilo, Silva Eduardo C A, Cárcano Flavio M, Zaia Maurício G, Lopes Luiz F, Scapulatempo-Neto Cristovam, Pinheiro Céline
Molecular Oncology Research Center, Barretos Cancer Hospital, São Paulo, Brazil.
Department of Pathology, Barretos Cancer Hospital, São Paulo, Brazil.
Front Endocrinol (Lausanne). 2019 Jun 28;10:417. doi: 10.3389/fendo.2019.00417. eCollection 2019.
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.
睾丸生殖细胞肿瘤（TGCTs）是一组罕见的肿瘤，是年轻成年男性中最常见的实体恶性肿瘤。尽管这些肿瘤对铂类化疗反应良好，但一些患者对治疗难治，临床预后较差。在致癌作用和肿瘤发展过程中，癌细胞将能量代谢重编程为高糖酵解表型，这是癌症新出现的一个标志。这种现象被称为瓦尔堡效应或有氧糖酵解，涉及代谢相关蛋白的过度表达，如葡萄糖和单羧酸转运蛋白、pH调节剂和细胞内糖酵解酶。TGCTs的代谢特征鲜少被研究，最近，癌细胞的这种代谢重布线已与这些肿瘤的侵袭性临床病理特征相关联。TGCTs中单羧酸转运蛋白4（MCT4）的过度表达已被指出是一个不良预后因素，也是一个有前景的治疗靶点。因此，本研究的主要目的是评估关键代谢相关蛋白在TGCTs中的预后价值。在148例成年男性TGCT患者中评估了CD44（作为单羧酸转运蛋白伴侣）、葡萄糖转运蛋白1（GLUT1）、碳酸酐酶IX（CAIX）、己糖激酶II（HKII）和乳酸脱氢酶V（LDHV）的免疫组化表达，并将其与临床病理参数相关联。此外，还评估了配对的正常组织。样本包括75例精原细胞瘤和73例非精原细胞瘤肿瘤。与配对的正常样本相比，恶性样本中GLUT1和CD44表达显著增加。相反，恶性样本中HKII和LDHV表达显著降低。关于临床病理值，CAIX表达与疾病复发显著相关，而HKII表达与TGCTs的侵袭性特征显著相关，包括更高分期和非精原细胞瘤组织学。总之，本研究为TGCTs的代谢特征带来了新见解，显示了与瓦尔堡效应相关蛋白表达的改变，以及高糖酵解和耐酸表型与侵袭性临床病理参数的关联。
