CXCR4, one of the receptors of CXCL12, is expressed on multiple cell types, including lymphocytes, hematopoietic stem cells, epithelial cells, and cancer cells [26]. The binding of CXCL12 to CXCR4 results in the activation of the CXCR4/CXCL12 axis and dissociation of the heterotrimeric protein complex (Gαβγ) to Gα and Gβγ subunits, which activate a number of signaling pathways including MAPK, PI3K/AKT, and NF-κB. Ultimately, cell growth, protein synthesis, and inflammation are upregulated. In addition to this change, the E-cadherin will be decreased and the expression of N-cadherin and vimentin will be raised; simultaneously, those cells lose cell polarity and tight intercellular junction while gaining the features of a mesenchymal cell and the capability of migration and invasion. This positive feedback loop stimulates more CXCL12 to be released into the TME to activate the CXCR4/CXCL12 axis.