AGER and cancer: Most cancer cells not only overexpress RAGE, but also release abundant concentrations of its ligands from the tumor hypoxic core, which can closely interact in both autocrine and paracrine manners, leading to an increased leukocyte activation, apoptosis, and recruitment of stromal cells into the TME in a RAGE-dependent manner, as well as mediating fibro-inflammatory phenotypical changes, a complex process called desmoplasia [194].