bims-stacyt 2021-08-08 papers

Biochem Soc Trans. 2021 Aug 02. pii: BST20210496. [Epub ahead of print]

Are cachexia-associated tumors transmitTERS of ER stress?

Ana Sayuri Yamagata, Paula Paccielli Freire.

Cancer cachexia is associated with deficient response to chemotherapy. On the other hand, the tumors of cachectic patients remarkably express more chemokines and have higher immune infiltration. For immunogenicity, a strong induction of the unfolded protein response (UPR) is necessary. UPR followed by cell surface exposure of calreticulin on the dying tumor cell is essential for its engulfment by macrophages and dendritic cells. However, some tumor cells upon endoplasmic reticulum (ER) stress can release factors that induce ER stress to other cells, in the so-called transmissible ER stress (TERS). The cells that received TERS produce more interleukin 6 (IL-6) and chemokines and acquire resistance to subsequent ER stress, nutrient deprivation, and genotoxic stress. Since ER stress enhances the release of extracellular vesicles (EVs), we suggest they can mediate TERS. It was found that ER stressed cachexia-inducing tumor cells transmit factors that trigger ER stress in other cells. Therefore, considering the role of EVs in cancer cachexia, the release of exosomes can possibly play a role in the process of blunting the immunogenicity of the cachexia-associated tumors. We propose that TERS can cause an inflammatory and immunosuppressive phenotype in cachexia-inducing tumors.

Keywords: ER stress; cachexia; cancer; immunology; tumor microenvironment

DOI: https://doi.org/10.1042/BST20210496

Cell Metab. 2021 Jul 30. pii: S1550-4131(21)00331-4. [Epub ahead of print]

Exercise-induced angiogenesis is dependent on metabolically primed ATF3/4+ endothelial cells.

Zheng Fan, Guillermo Turiel, Raphaela Ardicoglu, Moheb Ghobrial, Evi Masschelein, Tea Kocijan, Jing Zhang, Ge Tan, Gillian Fitzgerald, Tatiane Gorski, Abdiel Alvarado-Diaz, Paola Gilardoni, Christopher M Adams, Bart Ghesquière, Katrien De Bock.

Exercise is a powerful driver of physiological angiogenesis during adulthood, but the mechanisms of exercise-induced vascular expansion are poorly understood. We explored endothelial heterogeneity in skeletal muscle and identified two capillary muscle endothelial cell (mEC) populations that are characterized by differential expression of ATF3/4. Spatial mapping showed that ATF3/4+ mECs are enriched in red oxidative muscle areas while ATF3/4low ECs lie adjacent to white glycolytic fibers. In vitro and in vivo experiments revealed that red ATF3/4+ mECs are more angiogenic when compared with white ATF3/4low mECs. Mechanistically, ATF3/4 in mECs control genes involved in amino acid uptake and metabolism and metabolically prime red (ATF3/4+) mECs for angiogenesis. As a consequence, supplementation of non-essential amino acids and overexpression of ATF4 increased proliferation of white mECs. Finally, deleting Atf4 in ECs impaired exercise-induced angiogenesis. Our findings illustrate that spatial metabolic angiodiversity determines the angiogenic potential of muscle ECs.

Keywords: amino acid metabolism; endothelial heterogeneity; endothelial metabolism; exercise; muscle angiogenesis; single-cell RNA-seq

DOI: https://doi.org/10.1016/j.cmet.2021.07.015

Technol Cancer Res Treat. 2021 Jan-Dec;20:20 15330338211036304

Hypoxia and the Tumor Microenvironment.

Yue Li, Long Zhao, Xiao-Feng Li.

Hypoxia is an important feature of the tumor microenvironment, and is closely associated with cell proliferation, angiogenesis, metabolism and the tumor immune response. All these factors can further promote tumor progression, increase tumor aggressiveness, enhance tumor metastatic potential and lead to poor prognosis. In this review, these effects of hypoxia on tumor biology will be discussed, along with their significance for tumor detection and treatment.

Keywords: angiogenesis; hypoxia; hypoxia-targeted therapy; metabolism; tumor microenvironment

DOI: https://doi.org/10.1177/15330338211036304