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

Table 1 Interplay between hypoxia, angiogenesis, and endoplasmic reticulum stress in carcinogenesis

Link (biological connection)	Experimental evidence	Clinical evidence
Hypoxia → HIF stabilization → VEGF-driven angiogenesis	When tumors become hypoxic, HIF-1 levels rise and activate several angiogenic genes, especially VEGF and its related signaling molecules. These factors help new blood vessels sprout, ensuring that the growing tumor receives enough oxygen and nutrients. As a result, hypoxia-induced HIF-1 activation directly drives VEGF-mediated angiogenesis, which supports tumor survival, progression, and metastasis[148,151]	Tumor IHC studies show high HIF-1α and VEGF expression correlating with high microvessel density, advanced tumor stage, and poor survival rate. HIF-1α showed a positive correlation with VEGF expression in colorectal cancer[172]
Hypoxia → ER stress → UPR activation (IRE1, PERK, ATF6)	Hypoxia disrupts ER protein folding and activates UPR pathways. Hypoxic cells show increased BiP, CHOP, ATF4, and XBP1s. Blocking UPR increases hypoxia-induced cell death[173]	Hypoxia-linked activation of UPR markers (GRP78, PERK, IRE1α, ATF6), which correlates with aggressive behavior, poor prognosis, and therapy resistance[174]
PERK-ATF4 ↔ HIF (cooperative signaling)	PERK activation induces ATF4, which cooperates with HIF to support metabolic adaptation (e.g., CA9 regulation). Inhibiting PERK or ATF4 reduces hypoxic survival[175]	Clinical studies summarized in[175] demonstrate that patient tumors exhibit co-expression of hypoxia (HIF-1α) and UPR markers (GRP78, PERK, ATF4, XBP1s) in aggressive, therapy-resistant regions, correlating with poor clinical outcomes
IRE1-XBP1 interaction with HIF to promote survival/angiogenesis	XBP1s interacts with HIF to enhance pro-survival and angiogenic programs. Blocking IRE1/XBP1 sensitizes cells to hypoxia[175]	Patient tumors with concurrent activation of the IRE1-XBP1 arm of the UPR and HIF-1α signaling exhibit increased angiogenesis, hypoxia tolerance, and therapy resistance, correlating with aggressive disease and poor prognosis[175]
UPR (ER stress) → increased angiogenic signaling	UPR activation upregulates VEGF, IL-8, and other angiogenic factors. Blocking UPR decreases the tumor angiogenesis in vivo[176]	Clinical observation reveals that tumors with elevated UPR markers (GRP78, PERK, XBP1) exhibit increased HIF-1α and VEGF expression, linking ER stress to enhanced angiogenic signaling and aggressive tumor behavior[174]
Hypoxia + ER stress → therapy resistance and poorer prognosis	Hypoxia and ER stress synergize to induce UPR-dependent autophagy, which promotes tumor cell survival and therapy resistance[174]	High HIF-1α and combined hypoxia/UPR signatures in tumors associate with advanced disease, metastasis, and poor survival rate[172]

VEGF: Vascular endothelial growth factor; UPR: Unfolded protein response; ER: Endoplasmic reticulum; HIF: Hypoxia inducible factor; IL-8: Interleukin-8; IHC: Immunohistochemistry.