The ER stress response mediator ERO1 triggers cancer metastasis by favoring the angiogenic switch in hypoxic conditions

Abstract

SummarySolid tumors are often characterized by a hypoxic microenvironment which contributes, through the hypoxia-inducible factor HIF-1, to the invasion-metastasis cascade. Endoplasmic reticulum (ER) stress also leads tumor cells to thrive and spread by inducing a transcriptional and translational program, the Unfolded Protein Response (UPR), aimed at restoring ER homeostasis. We studied ERO1 alpha (henceforth ERO1), a protein disulfide oxidase with the tumor-relevant characteristic of being positively regulated by both ER stress and hypoxia. Analysis of the redox secretome indicated that pro-angiogenic HIF-1 targets, were blunted in ERO1-devoid breast cancer cells under hypoxic conditions. ERO1 deficiency reduced tumor cell migration and lung metastases by impinging on tumor angiogenesis, negatively regulating the upstream ATF4/CHOP branch of the UPR and selectively impeding oxidative folding of angiogenic factors, among which VEGF-A. Thus, ERO1 deficiency acted synergistically with the otherwise feeble curative effects of anti-angiogenic therapy in aggressive breast cancer murine models and it might be exploited to treat cancers with pathological HIF-1-dependent angiogenesis. Furthermore, ERO1 levels are higher in the more aggressive basal breast tumors and correlate inversely with the disease- and metastasis-free interval of breast cancer patients. Thus, taking advantage of our in vitro data on ERO1-regulated gene products we identified a gene set associated with ERO1 expression in basal tumors and related to UPR, hypoxia, and angiogenesis, whose levels might be investigated in patients as a hallmark of tumor aggressiveness and orient those with lower levels toward an effective anti-angiogenic therapy.

The regulation of Ero1-alpha in homocysteine-induced macrophage apoptosis and vulnerable plaque formation in atherosclerosis

“…On the other hand, Ero1α, as a link of ER stress and ROS, can also regulate Chop expression in some conditions. For example, in breast tumor, CHOP was downregulated in ERO1α KO conditions under hypoxia, and further analysis showed steady increases in CHOP in WT cells during hypoxia that was not observed in ERO1α KO cells, implying a feedback loop between ERO1α and the upstream transcription factor CHOP [ [47]]. In the present study, we found that Chop expression was significantly up-regulated by Hcy at a time and dose dependent manner in mouse peritoneal macrophages, in line with the upregulation of Ero1α.…”

Upregulation of microfibrillar‑associated protein 2 is closely associated with tumor angiogenesis and poor prognosis in hepatocellular carcinoma

“…Angiogenesis stimulating factors include a class of cytokines known as antigenic growth factors, which act to stimulate the formation of blood vessels ( 31 ). At present, angiogenic factors such as platelet-derived growth factor, fibroblast growth factor, transforming growth factor and VEGFA have been discovered ( 32 ), of which VEGFA plays a key role in tumor angiogenesis ( 33 ). When tumor cells develop, their expression levels will generally rise quickly.…”

Regulation of redox signaling in HIF‐1‐dependent tumor angiogenesis

“…In vivo, ERO1-deficient breast cancer xenografts show reduced ability to generate lung metastases, together with a decreased vasculogenesis in the primary tumors, suggesting that ERO1 inhibition might represent a good tool to selectively impair angiogenesis of solid tumors and limit metastases [45] [52].…”