bims-stacyt 2020-10-04 papers

bims-stacyt

Biomed News

on Metabolism and the paracrine crosstalk between cancer and the organism

Issue of 2020–10–04
six papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge

Mechanisms of intermittent hypoxia-mediated macrophage activation - potential therapeutic targets for obstructive sleep apnoea.
The role of microenvironment in tumor angiogenesis.
Interleukin-8: A chemokine at the intersection of cancer plasticity, angiogenesis, and immune suppression.
Regulation of Cellular Immunity by Activating Transcription Factor 4.
M2‑TAM subsets altered by lactic acid promote T‑cell apoptosis through the PD‑L1/PD‑1 pathway.
STAT1 Dissociates Adipose Tissue Inflammation From Insulin Sensitivity in Obesity.

J Sleep Res. 2020 Sep 30. e13202

Mechanisms of intermittent hypoxia-mediated macrophage activation - potential therapeutic targets for obstructive sleep apnoea.

Susan F Fitzpatrick, Ailbhe D King, Cliona O'Donnell, Helen M Roche, Silke Ryan.

  Intermittent hypoxia (IH) plays a key role in the pathogenesis of insulin resistance (IR) in obstructive sleep apnoea (OSA). IH induces a pro-inflammatory phenotype of the adipose tissue with M1 macrophage polarisation, subsequently impeding adipocyte insulin signalling, and these changes are in striking similarity to those seen in obesity. However, the detailed molecular mechanisms of IH-induced macrophage polarisation are unknown and identification of same should lead to the identification of novel therapeutic targets. In the present study, we tested the hypothesis that IH acts through similar mechanisms as obesity, activating Toll-like-receptor (TLR)4/nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) and nucleotide-binding domain (NOD)-like receptor protein 3 (NLRP3) signalling pathways leading to the upregulation and secretion of the key cytokines interleukin (IL)-1β and IL-6. Bone-marrow derived macrophages (BMDMs) from lean and obese C57BL/6 male mice were exposed to a state-of-the-art in vitro model of IH. Independent of obesity, IH led to a pro-inflammatory M1 phenotype characterised by increased inducible nitric oxide synthase and IL-6 mRNA expression, robust increase in NF-κB DNA-binding activity and IL-6 secretion. Furthermore, IH significantly increased pro-IL-1β mRNA and protein expression and mature IL-1β secretion compared to control treatment. Providing mechanistic insight, pre-treatment with the TLR4 specific inhibitor, TAK-242, prevented IH-induced M1 polarisation and upregulation of IL-1β mRNA and pro-IL-1β protein expression. Moreover, IH-induced increase in IL-1β secretion was prevented in BMDMs isolated from NLRP3 knockout mice. Thus, targeting TLR4/NF-κB and NLRP3 signalling pathways may provide novel therapeutic options for metabolic complications in OSA.

Keywords:  IL-1β; NLRP3 inflammasome; Toll-like-receptor 4; intermittent hypoxia; macrophages; obstructive sleep apnoea

DOI:  https://doi.org/10.1111/jsr.13202
J Exp Clin Cancer Res. 2020 Sep 30. 39(1): 204

The role of microenvironment in tumor angiogenesis.

Xianjie Jiang, Jie Wang, Xiangying Deng, Fang Xiong, Shanshan Zhang, Zhaojian Gong, Xiayu Li, Ke Cao, Hao Deng, Yi He, Qianjin Liao, Bo Xiang, Ming Zhou, Can Guo, Zhaoyang Zeng, Guiyuan Li, Xiaoling Li, Wei Xiong.

  Tumor angiogenesis is necessary for the continued survival and development of tumor cells, and plays an important role in their growth, invasion, and metastasis. The tumor microenvironment-composed of tumor cells, surrounding cells, and secreted cytokines-provides a conducive environment for the growth and survival of tumors. Different components of the tumor microenvironment can regulate tumor development. In this review, we have discussed the regulatory role of the microenvironment in tumor angiogenesis. High expression of angiogenic factors and inflammatory cytokines in the tumor microenvironment, as well as hypoxia, are presumed to be the reasons for poor therapeutic efficacy of current anti-angiogenic drugs. A combination of anti-angiogenic drugs and antitumor inflammatory drugs or hypoxia inhibitors might improve the therapeutic outcome.

Keywords:  Angiogenic factor; Hypoxia inhibitor; Inflammatory factor; Tumor angiogenesis; Tumor microenvironment

DOI:  https://doi.org/10.1186/s13046-020-01709-5
Pharmacol Ther. 2020 Sep 24. pii: S0163-7258(20)30222-9. [Epub ahead of print] 107692

Interleukin-8: A chemokine at the intersection of cancer plasticity, angiogenesis, and immune suppression.

Kristen Fousek, Lucas A Horn, Claudia Palena.

  Tumor progression relies on the ability of cancer cells to effectively invade surrounding tissues and propagate. Among the many mechanisms that contribute to tumor progression is the epithelial-to-mesenchymal transition (EMT), a phenotypic plasticity phenomenon that increases the cancer cells' motility and invasiveness and influences their surrounding microenvironment by promoting the secretion of a variety of soluble factors. One such factor is IL-8, a chemokine with multiple pro-tumorigenic roles within the tumor microenvironment (TME), including stimulating proliferation or transformation of tumor cells into a migratory or mesenchymal phenotype. Further, IL-8 can increase tumor angiogenesis or recruit larger numbers of immunosuppressive cells to the tumor. Prognostically, observations in many tumor types show that patients with higher levels of IL-8 at baseline experience worse clinical outcomes. Additionally, studies have shown that the chemokine directly contributes to the development of resistance to both chemotherapy and molecularly targeted agents. More recently, clinical studies evaluating levels of IL-8 in patients receiving immune checkpoint inhibition (ICI) therapy deduced that myeloid tumor infiltration driven by IL-8 contributes to resistance to ICI agents and that peripheral IL-8 can predict outcomes to ICI therapy. Further, pre-clinical data demonstrate that targeting IL-8 or its receptors enables improved tumor killing by immune cells, and treatment strategies combining blockade of the IL-8/IL-8R axis with ICI ultimately improve anti-tumor efficacy. Based on these results and the prognostic capacity of IL-8, there are a number of ongoing clinical trials evaluating the addition of IL-8 targeting strategies to immune-based therapies.

Keywords:  IL-8; Therapeutic resistance; Tumor microenvironment; Tumor progression

DOI:  https://doi.org/10.1016/j.pharmthera.2020.107692
Immunol Lett. 2020 Sep 28. pii: S0165-2478(20)30385-0. [Epub ahead of print]

Regulation of Cellular Immunity by Activating Transcription Factor 4.

Debasmita Mukherjee, Lena S Bercz, Molly A Torok, Thomas A Mace.

  Activating transcription factor 4 (ATF4) is a DNA binding transcription factor belonging to the family of basic Leucine zipper proteins. ATF4 can be activated in response to multiple cellular stress signals including endoplasmic reticulum stress in the event of improper protein folding or oxidative stress because of mitochondrial dysfunction as well as hypoxia. There are multiple downstream targets of ATF4 that can coordinate the regulation between survival and apoptosis of a cell based on time and exposure to stress. ATF4, therefore, has a broad range of control that results in the modulation of immune cells of the innate and adaptive responses leading to regulation of the cellular immunity. Studies provide evidence that ATF4 can regulate immune cells such as macrophages, T cells, B cells, NK cells and dendritic cells contributing to progression of disease. Immune cells can be exposed to stressed environment in the event of a pathogen attack, infection, inflammation, or in the tumor microenvironment leading to increased ATF4 activity to regulate these responses. ATF4 can further control differentiation and maturation of different immune cell types becoming a determinant of effective immune regulation. Additionally, ATF4 has been heavily implicated in rendering effector immune cells dysfunctional that are used to target tumorigenesis. Therefore, there is a need to evaluate where the literature stands in understanding the overall role of ATF4 in regulating cellular immunity to identify therapeutic targets and generalized mechanisms for different disease progressions.

Keywords:  ATF4; Cellular Immunity; ER stress; Unfolded protein response

DOI:  https://doi.org/10.1016/j.imlet.2020.09.006
Oncol Rep. 2020 Nov;44(5): 1885-1894

M2‑TAM subsets altered by lactic acid promote T‑cell apoptosis through the PD‑L1/PD‑1 pathway.

Tao Shan, Shuo Chen, Xi Chen, Tao Wu, Yi Yang, Shunle Li, Jiancang Ma, Jing Zhao, Wanrun Lin, Wei Li, Xijuan Cui, Ya'an Kang.

The aim of the study was to investigate the effects of lactic acid on the phenotypic polarization and immune function of macrophages. The human monocyte/macrophage cell line, THP‑1, was selected and treated with lactic acid. Immunofluorescence staining, laser confocal microscopy, reverse‑transcription polymerase chain reaction (RT‑PCR), western blot, siRNA, and ELISA analyses were used to observe changes in the levels of cluster of differentiation (CD)68, CD163, hypoxia inducible factor (HIF)‑1α, and programmed death ligand‑1 (PD‑L1) as well as those of cytokines, tumor necrosis factor (TNF)‑α, interferon (IFN)‑γ, interleukin (IL)‑12, and IL‑10. THP‑1 macrophages and T cells were co‑cultured in vitro to observe the changes in proliferation and apoptosis of T cells. The results showed that, lactic acid (15 mmol/l) significantly upregulated the expression of the macrophage M2 marker CD163 (P<0.05), cytokines, IFN‑γ and IL‑10, secreted by M2‑tumor‑associated macrophages (TAM, P<0.05), and HIF‑1α and PD‑L1 (P<0.05), and downregulated the expression of cytokines, TNF‑α and IL‑12, secreted by M1‑TAM (P<0.05). Redistribution of M2‑TAM subsets and PD‑L1 expression was reversed after further transfection of THP‑1 cells with HIF‑1α siRNA (P<0.05). After co‑culturing, T‑cell proliferation was inhibited and apoptosis was promoted. In summary, modulation of lactic acid level can redistribute M2‑TAM subsets and upregulate PD‑L1 to assist tumor immune escape. The HIF‑1α signaling pathway may participate in this process, revealing that macrophages, as 'checkpoints' in organisms, are links that connect the immune status and tumor evolution, and can be used as a target in tumor treatment.

DOI: https://doi.org/10.3892/or.2020.7767
Diabetes. 2020 Sep 29. pii: db200384. [Epub ahead of print]

STAT1 Dissociates Adipose Tissue Inflammation From Insulin Sensitivity in Obesity.

Aaron R Cox, Natasha Chernis, David A Bader, Pradip K Saha, Peter M Masschelin, Jessica B Felix, Robert Sharp, Zeqin Lian, Vasanta Putluri, Kimal Rajapakshe, Kang Ho Kim, Dennis T Villareal, Reina Armamento-Villareal, Huaizhu Wu, Cristian Coarfa, Nagireddy Putluri, Sean M Hartig.

Obesity fosters low-grade inflammation in white adipose tissue (WAT) that may contribute to the insulin resistance that characterizes type 2 diabetes mellitus (T2DM). However, the causal relationship of these events remains unclear. The established dominance of signal transducer and activator of transcription 1 (STAT1) function in the immune response suggests an obligate link between inflammation and the co-morbidities of obesity. To this end, we sought to determine how STAT1 activity in white adipocytes affects insulin sensitivity. STAT1 expression in WAT inversely correlated with fasting plasma glucose in both obese mice and humans. Metabolomic and gene expression profiling established STAT1 deletion in adipocytes (STAT1 a-KO ) enhanced mitochondrial function and accelerated TCA cycle flux coupled with reduced fat cell size in subcutaneous WAT depots. STAT1 a-KO reduced WAT inflammation, but insulin resistance persisted in obese mice. Rather, elimination of type I cytokine interferon gamma (IFNγ) activity enhanced insulin sensitivity in diet-induced obesity. Our findings reveal a permissive mechanism that bridges WAT inflammation to whole-body insulin sensitivity.

DOI: https://doi.org/10.2337/db20-0384