Cancer stem cell plasticity drives therapy resistance in colorectal cancer

Figure 2 Molecular mechanisms driving cancer stem cell plasticity and therapy resistance in colorectal cancer. Multiple developmental signaling pathways, including Wnt/β-catenin, Notch, Hedgehog, phosphatidylinositol 3-kinase/protein kinase B/mechanistic target of rapamycin, and transforming growth factor-β signaling, cooperatively regulate cancer stem cell (CSC) maintenance, self-renewal, and phenotypic plasticity. The tumor microenvironment, composed of cancer-associated fibroblasts, immune cells, endothelial cells, cytokines, and extracellular matrix, further supports CSC survival and stemness. Additional mechanisms, including enhanced DNA damage repair, anti-apoptotic signaling, metabolic reprogramming, and epigenetic regulation, promote resistance to chemotherapy and radiotherapy, leading to minimal residual disease, tumor recurrence, and metastasis. CSC: Cancer stem cell; PI3K: Phosphatidylinositol 3-kinase; AKT: Protein kinase B; mTOR: Mechanistic target of rapamycin; TGF: Transforming growth factor; EMT: Epithelial-mesenchymal transition; CAF: Cancer-associated fibroblast; ECM: Extracellular matrix; OXPHOS: Oxidative phosphorylation.