bims-stacyt 2021-07-11 papers

FEBS J. 2021 Jul 06.

Regulation of redox signaling in HIF1-dependent tumor angiogenesis.

Valeria Manuelli, Chiara Pecorari, Giuseppe Filomeni, Ester Zito.

Angiogenesis is the process of blood vessel growth. The angiogenic switch consists of new blood vessel formation that, in carcinogenesis, can lead to the transition from a harmless cluster of dormant cells to a large tumorigenic mass with metastatic potential. Hypoxia, i.e. the scarcity of oxygen, is a hallmark of solid tumors to which they adapt by activating hypoxia-inducible factor-1 (HIF-1), a transcription factor triggering de novo angiogenesis. HIF-1 and the angiogenic molecules that are expressed upon its activation are modulated by redox status. Modulations of the redox environment can influence the angiogenesis signaling at different levels, thereby impinging on the angiogenic switch. This review provides a molecular overview of the redox-sensitive steps in angiogenic signaling, the main molecular players involved and their crosstalk with the unfolded protein response (UPR). New classes of inhibitors of these modulators which might act as antiangiogenic drugs in cancer are also discussed.

Keywords: ER stress; ERO1; HIF-1; UPR; angiogenesis; hypoxia; metastasis

DOI: https://doi.org/10.1111/febs.16110

Cell Mol Immunol. 2021 Jul 08.

The therapeutic implications of immunosuppressive tumor aerobic glycolysis.

Bradley I Reinfeld, W Kimryn Rathmell, Tae Kon Kim, Jeffrey C Rathmell.

In 2011, Hanahan and Weinberg added "Deregulating Cellular Energetics" and "Avoiding Immune Destruction" to the six previous hallmarks of cancer. Since this seminal paper, there has been a growing consensus that these new hallmarks are not mutually exclusive but rather interdependent. The following review summarizes how founding genetic events for tumorigenesis ultimately increase tumor cell glycolysis, which not only supports the metabolic demands of malignancy but also provides an immunoprotective niche, promoting malignant cell proliferation, maintenance and progression. The mechanisms by which altered metabolism contributes to immune impairment are multifactorial: (1) the metabolic demands of proliferating tumor cells and activated immune cells are similar, thus creating a situation where immune cells may be in competition for key nutrients; (2) the metabolic byproducts of aerobic glycolysis directly inhibit antitumor immunity while promoting a regulatory immune phenotype; and (3) the gene programs associated with the upregulation of glycolysis also result in the generation of immunosuppressive cytokines and metabolites. From this perspective, we shed light on important considerations for the development of new classes of agents targeting cancer metabolism. These types of therapies can impair tumor growth but also pose a significant risk of stifling antitumor immunity.

Keywords: cancer; glycolysis; immunology; metabolism

DOI: https://doi.org/10.1038/s41423-021-00727-3

Front Cell Dev Biol. 2021 ;9 631413

Role of VEGFR2 in Mediating Endoplasmic Reticulum Stress Under Glucose Deprivation and Determining Cell Death, Oxidative Stress, and Inflammatory Factor Expression.

Bohan Xu, Linbin Zhou, Qishan Chen, Jianing Zhang, Lijuan Huang, Shasha Wang, Zhimin Ye, Xiangrong Ren, Yu Cai, Lasse Dahl Jensen, Weirong Chen, Xuri Li, Rong Ju.

Retinal pigment epithelium (RPE), a postmitotic monolayer located between the neuroretina and choroid, supports the retina and is closely associated with vision loss diseases such as age-related macular degeneration (AMD) upon dysfunction. Although environmental stresses are known to play critical roles in AMD pathogenesis and the roles of other stresses have been well investigated, glucose deprivation, which can arise from choriocapillary flow voids, has yet to be fully explored. In this study, we examined the involvement of VEGFR2 in glucose deprivation-mediated cell death and the underlying mechanisms. We found that VEGFR2 levels are a determinant for RPE cell death, a critical factor for dry AMD, under glucose deprivation. RNA sequencing analysis showed that upon VEGFR2 knockdown under glucose starvation, endoplasmic reticulum (ER) stress and unfolded protein response (UPR) are reduced. Consistently, VEGFR2 overexpression increased ER stress under the same condition. Although VEGFR2 was less expressed compared to EGFR1 and c-Met in RPE cells, it could elicit a higher level of ER stress induced by glucose starvation. Finally, downregulated VEGFR2 attenuated the oxidative stress and inflammatory factor expression, two downstream targets of ER stress. Our study, for the first time, has demonstrated a novel role of VEGFR2 in RPE cells under glucose deprivation, thus providing valuable insights into the mechanisms of AMD pathogenesis and suggesting that VEGFR2 might be a potential therapeutic target for AMD prevention, which may impede its progression.

Keywords: ER stress; VEGFR2; advanced technology; eye diseases; glucose deprivation; translational vision science; visual development

DOI: https://doi.org/10.3389/fcell.2021.631413