Unravelling the pathways driving tumour growth and resistance

Abstract

Background: Cancer is a complex and adaptive disease characterised by uncontrolled cell proliferation, tissue invasion, and metastasis. Previously thought to be a genetic disease caused by DNA abnormalities, recent research demonstrates the critical role of metabolic reprogramming in cancer development. Cancer cells experience severe metabolic changes in the tumour microenvironment (TME), which include nutritional deprivation, hypoxia, and low pH. Main text: The Warburg effect is a dramatic shift in which cells rely on aerobic glycolysis instead of oxidative phosphorylation (OXPHOS) for rapid energy production and growth. MYC, an oncogene, and TP53, a tumour suppressor, regulate metabolic alterations by increasing glycolysis, glutaminolysis, and other pathways necessary for tumour survival. Mitochondrial failure causes genomic instability, cancer, and resistance to apoptosis, increasing reliance on glycolysis and glutaminolysis. Cancer stem cells (CSCs) and resistant tumour forms are metabolically flexible, allowing them to adapt to environmental changes. The TME regulates metabolic pathways that promote tumour growth, including HIFs and AMPK. Conclusion: Therapeutic drugs that target altered metabolic pathways, such as glycolytic enzyme inhibitors, glutaminolysis, and mitochondrial function, have shown promise in both preclinical and clinical studies. However, the metabolic flexibility of cancer cells and tumour heterogeneity make treatment problematic. Recent therapeutic strategies combining metabolic inhibitors, chemotherapy, and immunotherapy have yielded promising results.