Deciphering the interplay between hypoxia, angiogenesis, and endoplasmic reticulum stress in carcinogenesis: A narrative review

Figure 2 Diagram showing the interplay between hypoxia, endoplasmic reticulum stress, and angiogenesis in cancer progression: Under hypoxic conditions, cancer cells upregulate the expression of hypoxia inducible factor-1α and hypoxia inducible factor-2α, which in turn enhances vascular endothelial growth factor transcription, promoting angiogenesis. Simultaneously, hypoxia disrupts protein folding within the endoplasmic reticulum (ER), leading to the ER stress and activation of the unfolded protein response through its three primary signaling branches: PERK, IRE1, and ATF6 The PERK and IRE1 branches further contribute to vascular endothelial growth factor transcription and secretion, helping to regulate HIF-1 protein stability and thereby creating a feedback loop that supports tumor vascularization and survival under low-oxygen conditions. HIF: Hypoxia inducible factor; VEGF: Vascular endothelial growth factor; ER: Endoplasmic reticulum.