For example, cells localized closer to the necrotic core in a tumor experience lower O2 concentrations (<1%) and have higher levels of HIF expression and therefore higher levels of HIF-dependent pathways that promote cell migration and invasion, such as RhoA-ROCK (Gilkes et al., 2014), ITGA5 (Ju et al., 2017), ADAM12-HB-EGF-EGFR (Wang et al., 2021b), Notch (Chen et al., 2010), and miR-219-SMC4 (Chen et al., 2019), among others. Here, EGF is linked to neoplasm.