Journal of Cancer Research
- ISSN: 2578-3726
Alexandre Tavartkiladze, Gaiane Simonia, Ruite Lou, Dinara Kasradze, Pati Revazishvili, Maia Maisuradze, Rusudan Khutsishvili, Tatia Potskhoraia, Tamar Japaridze, Irine Andronikashvili, Prada Noyade and Tamaz Mamukishvili
Lung adenocarcinoma, a subtype of non-small cell lung cancer (NSCLC), exhibits profound metabolic reprogramming as it progresses, characterized by a shift from oxidative phosphorylation (OXPHOS) to glycolysis, even in the presence of oxygen. This phenomenon, known as the Warburg effect, enables cancer cells to meet their increased energy and biosynthetic demands, facilitating rapid proliferation and tumor progression. In this study, we compared the metabolic profiles of 150 patients, including 75 with stage 4 lung adenocarcinoma and 75 with early-stage disease (stage I and II), to investigate the dynamic metabolic changes occurring as the disease advances. We analyzed key glycolysis markers—glucose, lactate, and pyruvate—along with oxidative phosphorylation markers—β-hydroxybutyrate, acetoacetate, glutamine, and alanine. The findings revealed a significant increase in glycolysis markers in the stage 4 group, indicating a pronounced shift towards glycolysis. Concurrently, oxidative phosphorylation markers showed a marked reduction, reflecting mitochondrial dysfunction. Additionally, inflammatory cytokines (IL-6, IL-1Beta, TNF-alpha) and lactate dehydrogenase (LDH) were elevated in the advanced-stage patients, contributing to the pro-tumorigenic environment and promoting immune evasion and angiogenesis. Oxidative stress markers, such as melatonin and dopamine, were significantly reduced in stage 4 patients, further underscoring the role of oxidative stress in disease progression. The metabolic reprogramming in lung adenocarcinoma is tightly linked to the tumor microenvironment, supporting immune evasion and metastatic potential. These findings highlight the critical metabolic changes in advanced lung adenocarcinoma and underscore the potential for targeting glycolysis and related pathways as therapeutic strategies. The decline in oxidative phosphorylation and the increase in glycolysis markers suggest a metabolic threshold beyond which traditional anticancer treatments may offer diminishing returns, necessitating novel interventions to disrupt tumor metabolism and improve patient outcomes.
Highlights
• Metabolic Shift to Glycolysis: Lung adenocarcinoma cells demonstrate a significant shift from oxidative phosphorylation to glycolysis (Warburg effect), especially in advanced stages, allowing cancer cells to meet the increased energy and biosynthetic demands of rapid tumor growth.
• Increased Glycolysis Markers: Elevated levels of glycolysis markers such as glucose, lactate, and pyruvate were observed in stage 4 lung adenocarcinoma patients, indicating reliance on glycolysis for energy production.
• Inflammatory Cytokine Elevation: Advanced-stage lung adenocarcinoma patients exhibited higher levels of inflammatory cytokines, including IL-6, IL-1Beta, and TNF-alpha, contributing to tumor progression, immune evasion, and angiogenesis.
• Reduced Oxidative Phosphorylation: Markers of oxidative phosphorylation such as β-hydroxybutyrate, acetoacetate, glutamine, and alanine were significantly reduced in advanced-stage lung adenocarcinoma patients, indicating mitochondrial dysfunction and a shift away from oxidative metabolism.
• Oxidative Stress and Antioxidant Decline: A marked decrease in melatonin and dopamine levels suggests enhanced oxidative stress and weakened antioxidant defenses in advanced lung adenocarcinoma, further promoting tumor progression.
• Therapeutic Implications: Targeting glycolysis and related metabolic pathways, along with inflammatory cytokines, could provide novel therapeutic strategies to improve treatment outcomes in advanced lung adenocarcinoma.