Fig. 3.

The different mechanisms of chemoresistance in CRC (Figure and Figure legend adapted from Samuel SM, et al., 2020) [245]. The mechanisms of cancer cell plasticity in therapeutic resistance mainly include; (1) the presence and influence of cancer stem cells (CSCs) that can initiate and re-populate tumors, (2) epithelial–to-mesenchymal transition (EMT), (3) tumor microenvironment (characterized by hypoxia, inflammation, autophagy, and presence of cancer-associated fibroblasts, immune cells such as tumor-associated macrophages, and tumor endothelial cells), (4) active DNA damage repair mechanisms, (5) altered/adaptive/aberrant metabolism (characterized by the Warburg effect, altered amino acid/protein/lipid and nucleotide metabolism, utilization of glutamine, and isoforms of metabolic enzymes that support cancer initiation, progression, and resistance to therapy), (6) variations in drug uptake and active drug extrusion systems (ATP binding cassette; ABC/multidrug transporters), (7) activation of oncogenic, pro-survival and anti-apoptotic signaling pathways (PI3K, phosphatidylinositol-3-kinase; Akt, protein kinase B; mTOR, mammalian target of rapamycin; MAPK, mitogen activated protein kinase; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B-cells; Wnt/β-catenin; JAK, janus kinase; STAT3, signal transducer and activator of transcription 3; HIF-1, hypoxia inducible factor 1 pathways), and (8) active drug detoxification and target alteration systems. Created with BioRender.com