NOTCH1 and hepatocellular carcinoma: For example, CAFs increase the secretion of CCL-2 to activate the Notch1/STAT3 pathway, which increases the expression of stem cell markers and upregulates the globulation rate in breast cancer.489 CAFs regulate TIC plasticity in HCC through c-Met/FRA1/HEY1 signaling.490 CAFs secrete high levels of IL-6 to activate Notch signaling through STAT3 Tyr705 phosphorylation, thus promoting the stem cell-like characteristics of HCC cells.491 Similar studies have shown that CAF-derived exons enhance colon stem cell resistance to 5-fluorouracil by activating the Wnt signaling pathway.492