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

Cancer cells face oxygen and nutrient shortages, driving vascular endothelial growth factor (VEGF)-mediated angiogenesis and increasing protein-folding demand, which triggers endoplasmic reticulum (ER) stress and activates the unfolded protein response (UPR) pathways. The UPR is triggered through three major sensors: IRE1, PERK, and ATF6. Simultaneously, hypoxia stabilizes hypoxia-inducible factor (HIF) genes, enabling tumors to adapt, promote angiogenesis, and enhance survival. This review aims to decode the interconnected roles of hypoxia, angiogenesis, and ER stress in carcinogenesis, with a specific focus on how HIF-regulated signaling integrates these pathways to support tumor progression and impact clinical behavior. Researchers have found that both the UPR and hypoxia pathways influence VEGF expression by increasing the transcription factors ATF-4 and XBP-1, respectively, and by enhancing the expression of HIF genes. HIF genes are known as one of the master regulators of angiogenesis. The PERK/eIF2α pathway, IRE-1, and ATF6, all three branches of the UPR response, also help cancer cells survive under hypoxic conditions. On one hand, where PERK increases the heterodimerization between α levels at the translational level, the IRE-1 branch increases its stabilization via a process known as regulated IRE-1-dependent decay, an endoribonuclease activity. Understanding this triad will support the development of targeted therapies, including HIF inhibitors, anti-angiogenic agents, and UPR modulators, as well as biomarker-based patient selection and combination treatment strategies. Integrating hypoxia, angiogenesis, and ER stress biology reveals critical insights for designing more precise and effective anticancer interventions.