bims-stacyt 2020-07-26 papers

Int J Mol Sci. 2020 Jul 17. pii: E5071. [Epub ahead of print]21(14):

Distinct Cargos of Small Extracellular Vesicles Derived from Hypoxic Cells and Their Effect on Cancer Cells.

Geoffroy Walbrecq, Christiane Margue, Iris Behrmann, Stephanie Kreis.

Hypoxia is a common hallmark of solid tumors and is associated with aggressiveness, metastasis and poor outcome. Cancer cells under hypoxia undergo changes in metabolism and there is an intense crosstalk between cancer cells and cells from the tumor microenvironment. This crosstalk is facilitated by small extracellular vesicles (sEVs; diameter between 30 and 200 nm), including exosomes and microvesicles, which carry a cargo of proteins, mRNA, ncRNA and other biological molecules. Hypoxia is known to increase secretion of sEVs and has an impact on the composition of the cargo. This sEV-mediated crosstalk ultimately leads to various biological effects in the proximal tumor microenvironment but also at distant, future metastatic sites. In this review, we discuss the changes induced by hypoxia on sEV secretion and their cargo as well as their effects on the behavior and metabolism of cancer cells, the tumor microenvironment and metastatic events.

Keywords: TME; biomarker; cancer; exosomes; extracellular vesicles; hypoxia; immunity

DOI: https://doi.org/10.3390/ijms21145071

ACS Nano. 2020 Jul 24.

Metabolic Modulation of the Tumor Microenvironment Leads to Multiple Checkpoint Inhibition and Immune Cell Infiltration.

David Kolb, Nagesh Kolishetti, Bapurao Surnar, Shrita Sarkar, Subham Guin, Anuj S Shah, Shanta Dhar.

Cancer cells are known to be glycolytic, driving increased glucose consumption and its conversion to lactate. This process modulates the tumor microenvironment (TME). In the TME, glycolytic activated immune cells often become anergic leading to an increase in the checkpoint proteins. Inhibiting glycolysis in tumor cells, and not immune cells, has the potential to attenuate checkpoint proteins. Most glycolytic inhibitors not only inhibit glycolysis of cancer but also of immune cells. Pyruvate dehydrogenase kinase 1 (PDK1) can be an important target to achieve tumor specific glycolysis inhibition. We report TME modulation by a mitochondrion-targeted nanoparticle (NP) of a PDK 1 inhibitor. We demonstrated that the targeted NP can bring alterations in TME which result in increased immunological activation against cancer cells. Here we show encouraging findings when this inhibitor was combined with anti-PD-1. This works provides a platform to bring therapeutic efficacy by selectively inhibiting glycolysis of cancer cells.

DOI: https://doi.org/10.1021/acsnano.9b10037

Stem Cell Res Ther. 2020 Jul 22. 11(1): 313

Small extracellular vesicles secreted by human iPSC-derived MSC enhance angiogenesis through inhibiting STAT3-dependent autophagy in ischemic stroke.

Yuguo Xia, Xiaozheng Ling, Guowen Hu, Qingwei Zhu, Juntao Zhang, Qing Li, Bizeng Zhao, Yang Wang, Zhifeng Deng.

BACKGROUND: Small extracellular vesicles (sEV) secreted by mesenchymal stem cells (MSC) derived from human induced pluripotent stem cells (iPSC, iMSC-sEV) are considered to have great potential in treating ischemic diseases. Angiogenesis play an important role in post-stroke recovery. However, no studies have yet been conducted to systemically examine the effect and the underlying mechanism of iMSC-sEV on angiogenesis under brain ischemia conditions.
METHODS: Ischemic stroke model was performed in rats induced by middle cerebral artery occlusion (MCAO), and the pro-angiogenic capacity of iMSC-sEV was measured. The in vitro effects of iMSC-sEV on the migration and tube formation of endothelial cells were investigated, respectively. Autophagy and autophagy-related signaling pathway were detected in vivo and in vitro.
RESULTS: We found that iMSC-sEV significantly reduced infarct volume, enhanced angiogenesis, and alleviated long-term neurological deficits in rats after stroke. We also demonstrated that iMSC-sEV increased migration and tube formation of endothelial cells in vitro. A further mechanism study revealed that the pro-angiogenic effect of iMSC-sEV was correlated with a reduction in autophagy. Furthermore, iMSC-sEV significantly activated signal transducer and activator of transcription 3 (STAT3), and suppression of STAT3 abolished iMSC-sEV-induced inhibition of autophagy and promotion of angiogenesis in vivo and in vitro.
CONCLUSIONS: Taken together, our data indicate that iMSC-sEV promote angiogenesis after ischemic stroke, potentially, by inhibiting autophagy, a process that is partially dependent on STAT3 activation.

Keywords: Angiogenesis; Autophagy; Human induced pluripotent stem cell-derived mesenchymal stem cells; Small extracellular vesicles

DOI: https://doi.org/10.1186/s13287-020-01834-0

Curr Cancer Drug Targets. 2020 Jul 19.

Tumor-induced Metabolism and T Cells Located in Tumor Environment.

Sara Iranparast, Sanaz Tayebi, Fatemeh Ahmadpour, Bahman Yousefi.

Several subtypes of T cells are located in a tumor environment, each of which supplies their energy using different metabolic mechanisms. Since the cancer cells require high levels of glucose, the conditions of food poverty in the tumor environment can cause inactivation of immune cells, especially the T-effector cells, due to the need for glucose in the early stages of these cells activity. Different signaling pathways such as PI3K-AKt-mTOR, MAPK, HIF-1α, etc active or inactive by the amount and type of energy source or oxygen levels that determine the fate of T cells in a cancerous environment. This review describes the metabolites in the tumor environment and their effects on the function of T cells. It also explains the signaling pathway of T cells in the tumor and normal conditions, due to the level of access to available metabolites and subtypes of T cells in the tumor environment.

Keywords: T lymphocytes; cancer; cytokines.; immune evasion; immunotherapy; metabolism

DOI: https://doi.org/10.2174/1568009620666200720010647