Differential expression of metabolic enzymes in testicular germ cell tumors: The impact of glycolytic metabolism in embryonal carcinoma histotype

Background: Testicular germ cell tumors are the most common solid malignancies in young men, with increasing incidence worldwide. Broadly classified into seminomas and non-seminomas, they exhibit distinct biological behaviors and responses to treatment. Although metabolic reprogramming is an acknowledged cancer hallmark, metabolic pathways in testicular germ cell tumors remain poorly understood.

Objectives: This study investigates the differential expression of metabolic markers (GLUT-1, MCT1, MCT4, LDHA, HIF-1α) and the epigenetic enzyme KDM3A across various testicular germ cell tumor subtypes, aiming to understand how glycolytic metabolism is related to each histotype and how it may impact tumor aggressiveness, correlating with patient outcomes.

Materials and methods: The study involved 111 testicular germ cell tumor individual tumor components from 90 patients diagnosed and treated at a comprehensive cancer center. Immunohistochemistry was used to ascertain biomarker expression, with a combined score of percentage of stained tumor cells and intensity of staining. In silico analysis of the Cancer Genome Atlas database was performed for additional validation, using cBioPortal. Statistical analyses included Mann-Whitney U, Kruskal-Wallis, and anova tests, with significance set at p < 0.05.

Results: Significant differences in the expression of metabolic markers across testicular germ cell tumor subtypes were disclosed. Embryonal carcinomas showed significantly higher expression of glycolytic markers (GLUT-1, MCT1, MCT4, LDHA) compared to other histotypes, suggesting heightened glycolytic activity. KDM3A depicted an inverse pattern, being significantly more expressed in seminomas. HIF-1α expression was generally low across all histological subtypes. Testicular germ cell tumors with necrosis showed higher expression of the metabolic players investigated.

Discussion and conclusion: We highlighted distinct metabolic profiles among testicular germ cell tumor subtypes, particularly the prominent glycolytic activity in embryonal carcinomas, with higher hypoxia and reliance on lactate transport. Metabolic reprogramming in embryonal carcinoma may underlie the high proliferation of this tumor subtype, which frequently discloses necrosis. These findings suggest that targeted agents such as MCT1 inhibitors may be particularly useful for treating testicular germ cell tumors containing high proportion of embryonal carcinoma.