Figure 8.

Colon cancer stem cells secrete exosomes containing signaling molecules, including miR-1246, TGF-β1, p-STAT3, β-catenin, and transform uncommitted macrophages and normal fibroblasts to M2 polarized tumor-associated macrophages (M2 TAM) and cancer-associated fibroblasts (CAF) respectively. M2 TAM and CAF promote cancer stemness and 5-FU resistance by secreting TGF-β1 and IL-6. TGF-β1 secreted by M2 TAM also facilitates CAF transformation; CAF secretes IL-6 to enhance M2 polarization and tumorigenesis. Ovatodiolide treatment prevents the generation of M2 TAM, CAF, and CSCs via reducing CSC derived exosomes and their cargoes.