Fig. 2

The illustration indicates interactions between CSCs and their environment: mechanical and chemical forces have their roles in this environment. For instance, inflammatory factors cause evaluation of STAT3, NF-κB, and AP-1 that result in stemness of CSCs. Sometimes, some changes in CSCs cause alterations in ECM that have indirect effects on CSCs like lactate emission from CSCs to ECM decreases environmental PH and then increases HIF-1α that results in elevation of urokinase-type plasminogen, cathepsins, and MMPs. Elevation of these substances causes degradation of the niche ( that is considered a mechanical change itself). On the other hand, CXCR4/CXCL12 axis triggers the PI3K/ AKT signaling pathway that evaluates EGF level in CSCs that binds to VEGFR and causes differentiation of CSCs to endothelial cells. Moreover, CXCR4/CXCL12 axis increases the MMPs level, which is an ECM remodeling factor in its own way. Mechanical forces (or signalings) from ECM are felt by integrin-β1 that starts FAK (maintenance of CSCs) and AKT/mTOR/SOX2 (expression of stemness markers such as CD133 and EpAM) signaling pathways