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. 2021 Nov 5;13(11):1879. doi: 10.3390/pharmaceutics13111879

Figure 2.

Figure 2

Simplified model of curcumin and flavonoids effects on the NSCLC microenvironment [83,119,148,158,159,162,168,170,174,175,186,187,188,189,190,191,192,193,194,195,196]. A necessary part of igenesis and CTC spreading is the interaction of NSCLC cells with tumour-associated cells. NSCLC cells recruit monocytes via IL-17 into tumour tissue. Signalling factors (e.g., IL-6, IL-8, TNF-α, and PGE2) produced in the tumour microenvironment stimulate monocyte differentiation into TAM2 (which support NSCLC cell proliferation, EMT, chemoresistance and immune resistance, and EM disruption). MDSCs recruited via IL-8 and TGF-β1 repress the cytotoxic effects of T cells against NSCLC cells and induce their differentiation into Treg cells that are responsible for the suppression of the host immune response. VEGF-recruited TECs affect EMT, chemoresistance, and the proliferation of NSCLC cells, recruit MDSCs and induce angiogenesis. IL-8-activated CAFs decrease the anticancer immune response (with the support of TAM2 and MDSCs) and repress T cells. CAFs stimulate EMT and induce NSCLC cell proliferation, migration, and drug resistance. Tumour-associated cells help sustain the tumour microenvironment and aggressive metastatic phenotype. TAM2, CAFs, and TECs are co-inducers of EMT and thereby CTC spreading, chemoresistance, and immune resistance. MDSCs and Treg cells repress the host immune response and thereby support CTC survival in the blood. Nevertheless, the anticancer effect of curcuminoids and flavonoids is not dependent on targeting of NSCLC cells, as they repress other important parts of the complex tumour ecosystem. The application of such agents is associated with stimulation of the immune system (higher levels of TAM1 and T cells; lower levels of Th1 cells, TAM2, and Treg cells; and lower recruitment of monocytes and MDSCs). Curcuminoids and flavonoids also decrease the levels of CAFs and TECs and repress their interaction with NSCLC cells. In addition, the application of curcuminoids and flavonoids leads to a decrease in the proliferation, survival, chemoresistance, immunoresistance, and migration ability of NSCLC cells. CAF, cancer-associated fibroblast; EM, extracellular matrix; EMT, epithelial–mesenchymal transition; EGF, endothelial growth factor; FasL, Fas ligand; IL-1β, interleukin 1β; IL-6, interleukin 6; IL-8, interleukin 8; PGE2, prostaglandin E2; NOS, nitric oxide species; ROS, reactive oxygen species; TAM1, tumour-associated macrophage M1; TAM2, tumour-associated macrophage M2; TEC, tumour endothelial cell; TGF-β1, transforming growth factor beta 1; Th1, T helper 1; Treg, regulatory T; TNF-α, tumour necrosis factor alpha; VEGF, vascular endothelial growth factor. Green arrow = induction/activation of factor/phenomenon/cell; red arrow = repression/inhibition of factor/phenomenon/cell; blue arrow = differentiation of immune cells; ↑ = curcumin/flavonoids activation/induction; ↓ = curcumin/flavonoids repression/inhibition.