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.

BackgroundMetabolic reprogramming is one of the hallmarks of cancer. The hyperglycolytic phenotype is often associated with the overexpression of metabolism-associated proteins, such as monocarboxylate transporters (MCTs). MCTs are little explored in germ cell tumors (GCTs), thus, the opportunity to understand the relevance of these metabolic markers and their chaperone CD147 in this type of tumor arises. The main aim of this study was to evaluate the expression of MCT1, MCT2, MCT4 and CD147 in testicular GCT samples and the clinicopathological significance of these metabolism related proteins.ResultsMCT1, MCT4 and CD147 were associated with higher stages, higher M and N stages and histological type, while MCT4 was also associated with higher risk stratification, presence of vascular invasion, and lower overall and event free survival. MCT4 silencing in JEG-3 had no significant effect in cell viability, proliferation and death, as well as extracellular levels of glucose and lactate. However, MCT4-silenced cells showed an increase in migration and invasion.ConclusionThe proteins herein studied, with the exception of MCT2, were associated with characteristics of worse prognosis, lower global and event free survival of patients with GCTs. Also, in vitro MCT4 silencing stimulated cell migration and invasion.Materials and MethodsImmunohistochemical expression was evaluated on samples from 149 adult patients with testicular GCT, arranged in Tissue Microarrays (TMAs), and associated with the clinicopathological data. Also, MCT4 silencing studies using siRNA were performed in JEG-3 cells.

BackgroundLocally advanced breast cancer often undergoes neoadjuvant chemotherapy (NAC), which allows in vivo evaluation of the therapeutic response. The determination of the pathological complete response (pCR) is one way to evaluate the response to neoadjuvant chemotherapy. However, the rate of pCR differs significantly between molecular subtypes and the cause is not yet determined. Recently, the metabolic reprogramming of cancer cells and its implications for tumor growth and dissemination has gained increasing prominence and could contribute to a better understanding of NAC. Thus, this study proposed to evaluate the expression of metabolism-related proteins and its association with pCR and survival rates.MethodsThe expression of monocarboxylate transporters 1 and 4 (MCT1 and MCT4, respectively), cluster of differentiation 147 (CD147), glucose transporter-1 (GLUT1) and carbonic anhydrase IX (CAIX) was analyzed in 196 locally advanced breast cancer samples prior to NAC. The results were associated with clinical-pathological characteristics, occurrence of pCR, disease-free survival (DFS), disease-specific survival (DSS) and overall survival (OS).ResultsThe occurrence of pCR was higher in the group of patients whith tumors expressing GLUT1 and CAIX than in the group without expression (27.8% versus 13.1%, p = 0.030 and 46.2% versus 13.5%, p = 0.007, respectively). Together with regional lymph nodes staging and mitotic staging, CAIX expression was considered an independent predictor of pCR. In addition, CAIX expression was associated with DFS and DSS (p = 0.005 and p = 0.012, respectively).ConclusionsCAIX expression was a predictor of pCR and was associated with higher DFS and DSS in locally advanced breast cancer patients subjected to NAC.

IntroductionCancer of unknown primary origin (CUP) is defined as metastatic cancer without identification of the primary site. Considering that only 15–20% of patients with CUP show a favorable outcome, identifying biomarkers may help improve the clinical management of patients who do not respond well to conventional therapies. In this context, the study of the metabolic profile of CUP may pave the way to establish new biomarkers and/or therapeutic targets; therefore, this study aimed to characterize the expression of metabolism-related proteins in CUP.Materials and MethodsThe expression of monocarboxylate transporters MCT1, MCT2 and MCT4, their chaperone CD147, the glucose transporter GLUT1 and the pH regulator CAIX was evaluated by immunohistochemistry in a series of 118 CUP patients, and the results were associated with the available clinicopathological information.ResultsThe metabolism-related proteins MCT1, MCT4, CD147, GLUT1 and CAIX were expressed in a critical portion of the CUP (approximately 20 to 70%). MCT1 and CD147 were both more frequently expressed in cases with lymph nodes as metastasis dominant sites (p = 0.001) as well as in samples from lymph nodes (p <0.001 and p = 0.002, respectively), while MCT1 expression was more frequently expressed in squamous cell carcinomas (p = 0.045). A higher overall survival was observed in patients with tumors positive for GLUT1 and CAIX expression (p = 0.011 and p = 0.041, respectively), but none of the proteins was an independent prognostic factor for overall survival in multivariable analysis.ConclusionThe results suggest that a portion of CUPs present a hyperglycolytic phenotype, which is associated with higher overall survival.