Figure 3.

Simplified model of curcumin and flavonoids action on NSCLC metastasis [83,190,223,224,229,230,231,236,237,238,239,240,242,243,244,245,246,247,248,249]. 1. NSCLC cells with a mesenchymal phenotype partially induced by TAM2, TECs, and CAFs migrate from tissue into blood vessels. 2. CTCs are transported (via passive transport) to distant metastatic site(s), and TECs can serve as guardians against anoikis apoptosis. 3. Infiltrating NSCLC cells revert to an epithelial phenotype via MErT (which possibly occurs in blood). 4. Dormant cancer cells activated by Wnt signalling start recruiting CAFs and TECs and form micrometastases. 5 Micrometastases stabilised by oxidative stress recruit tumour-associated cells to form macrometastases, at which point metastatic NSCLC can be diagnosed in patients. TECs and CAFs can support the formation of highly aggressive and metastatic CTC clusters. CAF, cancer-associated fibroblast; EMT, epithelial–mesenchymal transition; EGF, endothelial growth factor; IL-1β, interleukin 1β; IL-6, interleukin 6; IL-8, interleukin 8; PGE2, prostaglandin E2; ROS, reactive oxygen species; TAM2, tumour-associated macrophage M2 phenotype; TEC, tumour endothelial cell; TGF-β1, transforming growth factor beta 1; VEGF, vascular endothelial growth factor. Green arrow = induction/activation of factor/phenomenon; red arrow = repression/inhibition of factor/phenomenon; blue arrow = transition between individual steps of metastatic spread; ↓ = curcumin/flavonoids repression/inhibition.