The Warburg Effect Is Associated With Tumor Aggressiveness in Testicular Germ Cell Tumors

Abstract

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.

Orexin A-Mediated Modulation of Reproductive Activities in Testis of Normal and Cryptorchid Dogs: Possible Model for Studying Relationships Between Energy Metabolism and Reproductive Control

“…Our data are in agreement with previous data showing that the increase expression of Glut3 in the Leydig cells may be associated with cell hyperplasia and the relevant metabolic role of this glucose transporter in retained gonad (64). Interestingly, the cryptorchid condition predisposes to testicular germ cell tumors (TGCTs), characterized by metabolic hyper-glycolitic cell phenotype, promoting tumor development (65, 66).…”

β-Hexachlorocyclohexane: A Small Molecule with a Big Impact on Human Cellular Biochemistry

“…Highly aggressive tumors are likely to display a particular metabolic condition known as aerobic glycolysis or Warburg Effect, characterized by the preferential conversion of pyruvate to lactate, rather than to acetyl-CoA, even in normoxia [ 22 , 31 ]. In this context, the potential impact of β-HCH on cell metabolism was inspected by determining the lactate/pyruvate ratio in the culture media of cells treated or not with β-HCH.…”

Tumor cell‐derived angiopoietin‐like protein 2 establishes a preference for glycolytic metabolism in lung cancer cells

“…The NCI‐H460‐LNM35 (LNM35) line is a highly metastatic subline of the human large‐cell lung carcinoma cell line NCI‐H460 (H460) . Because enhanced glycolytic metabolism is reportedly associated with tumor aggressiveness, we asked whether LNM35 and H460 cells differed in terms of glycolytic metabolism by comparing glucose uptake and lactate production in both lines. Both glucose uptake and lactate production were significantly increased in LNM35 relative to H460 cells (Figure A,B), suggesting activation of glycolytic metabolism in the highly metastatic line.…”