Figure 1.

Mechanisms of action of metronomic chemotherapy (mCHT). The beneficial effects of mCHT are mediated by the inhibition of angiogenesis, the direct inhibition of tumour cell proliferation, and the stimulation of the immune system. Inhibition of angiogenesis plays a fundamental role in mCHT. The anti-angiogenic effects include direct inhibition of endothelial cells (ECs) proliferation via inhibition of pro-angiogenic factors, such as vascular-endothelial growth factor (VEGF), vascular endothelial growth factor receptor 2 (VEGF-R2), basic fibroblast growth factor (bFGF), and upregulation of endogenous angiogenic inhibitors, such as Thrombospondin 1 (TSP-1) endostatin, and platelet factor 4 (PF4), and inhibition of endogenous endothelial progenitor cells (EPCs) mobilization. Direct cytotoxic effects on tumor cells and decreased cancer stem cells (CSCs) population are also observed. mCHT also stimulates anticancer immunity by increasing cytotoxic activity of immune cell effectors and by inhibiting tumour-stromal activation. Figure created with BioRender.com.