bims-stacyt 2021-11-07 papers

bims-stacyt

Biomed News

on Metabolism and the paracrine crosstalk between cancer and the organism

Issue of 2021–11–07
thirteen papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge

HIF-1α Regulation of Cytokine Production following TLR3 Engagement in Murine Bone Marrow-Derived Macrophages Is Dependent on Viral Nucleic Acid Length and Glucose Availability.
PERK signaling through C/EBPδ contributes to ER stress-induced expression of immunomodulatory and tumor promoting chemokines by cancer cells.
Tumor-Secreted Lipids Induce ER Stress Response to Polarize Macrophages.
TGF-β1-containing exosomes from cardiac microvascular endothelial cells mediate cardiac fibroblast activation under high glucose conditions.
Lactate Is a Metabolic Mediator That Shapes Immune Cell Fate and Function.
The importance of hypoxia in radiotherapy for the immune response, metastatic potential and FLASH-RT.
PERK, Beyond an Unfolded Protein Response Sensor in Estrogen-induced Apoptosis in Endocrine-Resistant Breast Cancer.
A Forgotten Corner in Cancer Immunotherapy: The Role of Lipids.
Pro-angiogenic activity and vasculogenic mimicry in the tumor microenvironment by leptin in cancer.
Tumor PD-L1 and VEGF Expression, and CD8 T Cell Infiltration Predict Clinical Response to Immune Checkpoint Inhibitors in Non-small Cell Lung Cancer.
β2-Adrenoceptor Activation Stimulates IL-6 Production via PKA, ERK1/2, Src, and Beta-Arrestin2 Signaling Pathways in Human Bronchial Epithelia.
Targeting lactate metabolism and glycolytic pathways in the tumor microenvironment by natural products: A promising strategy in combating cancer.
Activation of Akt-mTORC1 signalling reverts cancer-dependent muscle wasting.

J Immunol. 2021 Nov 05. pii: ji2001282. [Epub ahead of print]

HIF-1α Regulation of Cytokine Production following TLR3 Engagement in Murine Bone Marrow-Derived Macrophages Is Dependent on Viral Nucleic Acid Length and Glucose Availability.

Duale Ahmed, Allan Humphrey, David Roy, Mary-Elizabeth Sheridan, Zoya Versey, Allison Jaworski, Alex Edwards, James Donner, Alfonso Abizaid, William Willmore, Ashok Kumar, Ashkan Golshani, Edana Cassol.

Hypoxia-inducible factor-1α (HIF-1α) is an important regulator of glucose metabolism and inflammatory cytokine production in innate immune responses. Viruses modulate HIF-1α to support viral replication and the survival of infected cells, but it is unclear if this transcription factor also plays an important role in regulating antiviral immune responses. In this study, we found that short and long dsRNA differentially engage TLR3, inducing distinct levels of proinflammatory cytokine production (TNF-α and IL-6) in bone marrow-derived macrophages from C57BL/6 mice. These responses are associated with differential accumulation of HIF-1α, which augments NF-κB activation. Unlike TLR4 responses, increased HIF-1α following TLR3 engagement is not associated with significant alterations in glycolytic activity and was more pronounced in low glucose conditions. We also show that the mechanisms supporting HIF-1α stabilization may differ following stimulation with short versus long dsRNA and that pyruvate kinase M2 and mitochondrial reactive oxygen species play a central role in these processes. Collectively, this work suggests that HIF-1α may fine-tune proinflammatory cytokine production during early antiviral immune responses, particularly when there is limited glucose availability or under other conditions of stress. Our findings also suggest we may be able to regulate the magnitude of proinflammatory cytokine production during antiviral responses by targeting proteins or molecules that contribute to HIF-1α stabilization.

DOI: https://doi.org/10.4049/jimmunol.2001282
Cell Death Dis. 2021 Nov 01. 12(11): 1038

PERK signaling through C/EBPδ contributes to ER stress-induced expression of immunomodulatory and tumor promoting chemokines by cancer cells.

Namratha Sheshadri, Dipak K Poria, Shikha Sharan, Ying Hu, Chunhua Yan, Vishal N Koparde, Kuppusamy Balamurugan, Esta Sterneck.

Cancer cells experience endoplasmic reticulum (ER) stress due to activated oncogenes and conditions of nutrient deprivation and hypoxia. The ensuing unfolded protein response (UPR) is executed by ATF6, IRE1 and PERK pathways. Adaptation to mild ER stress promotes tumor cell survival and aggressiveness. Unmitigated ER stress, however, will result in cell death and is a potential avenue for cancer therapies. Because of this yin-yang nature of ER stress, it is imperative that we fully understand the mechanisms and dynamics of the UPR and its contribution to the complexity of tumor biology. The PERK pathway inhibits global protein synthesis while allowing translation of specific mRNAs, such as the ATF4 transcription factor. Using thapsigargin and tunicamycin to induce acute ER stress, we identified the transcription factor C/EBPδ (CEBPD) as a mediator of PERK signaling to secretion of tumor promoting chemokines. In melanoma and breast cancer cell lines, PERK mediated early induction of C/EBPδ through ATF4-independent pathways that involved at least in part Janus kinases and the STAT3 transcription factor. Transcriptional profiling revealed that C/EBPδ contributed to 20% of thapsigargin response genes including chaperones, components of ER-associated degradation, and apoptosis inhibitors. In addition, C/EBPδ supported the expression of the chemokines CXCL8 (IL-8) and CCL20, which are known for their tumor promoting and immunosuppressive properties. With a paradigm of short-term exposure to thapsigargin, which was sufficient to trigger prolonged activation of the UPR in cancer cells, we found that conditioned media from such cells induced cytokine expression in myeloid cells. In addition, activation of the CXCL8 receptor CXCR1 during thapsigargin exposure supported subsequent sphere formation by cancer cells. Taken together, these investigations elucidated a novel mechanism of ER stress-induced transmissible signals in tumor cells that may be particularly relevant in the context of pharmacological interventions.

DOI: https://doi.org/10.1038/s41419-021-04318-y
Cancer Discov. 2021 Nov 05.

Tumor-Secreted Lipids Induce ER Stress Response to Polarize Macrophages.

Tumor-secreted lipids alter ER membrane composition to polarize tumor-associated macrophages (TAM).

DOI: https://doi.org/10.1158/2159-8290.CD-RW2021-160
Biochem Cell Biol. 2021 Nov 02. 1-7

TGF-β1-containing exosomes from cardiac microvascular endothelial cells mediate cardiac fibroblast activation under high glucose conditions.

Yan Zhang, Zhengru Zhu, Tingting Wang, Yuan Dong, Yanhong Fan, Dongdong Sun.

  Cardiac fibroblast (CF)-mediated extracellular matrix (ECM) remodeling is the key pathological basis for the occurrence and development of diabetic cardiomyopathy (DCM); its specific regulatory mechanisms have been widely studied but remain unclear. Exosomes are a type of stable signal transmission medium, and exosome-mediated cell-cell interactions play an important role in DCM. Endothelial cells form an important barrier between circulation and cardiomyocytes, in addition to being an important endocrine organ of the heart and an initial target for hyperglycemia, a key aspect in the development of DCM. We previously showed that exosomes derived from cardiac microvascular endothelial cells (CMECs) under high glucose conditions can be taken up by cardiomyocytes and regulate autophagy, apoptosis, and glucose metabolism. Consequently, in the present study, we focused on how exosomes mediate the interaction between CMECs and CFs. Surprisingly, exosomes derived from CMECs under high glucose were rich in TGF-β1 mRNA, which significantly promoted the activation of CFs. Additionally, exosomes derived from CMECs under high glucose conditions aggravated perivascular and interstitial fibrosis in mice treated with streptozotocin. Herein, we demonstrated for the first time the capacity of exosomes, released by CMECs under high glucose, to mediate fibroblast activation through TGF-β1 mRNA, which may be potentially beneficial in the development of exosome-targeted therapies to control DCM.

Keywords:  TGF-β1; cardiac fibroblast; cellule endothéliale; cell–cell interaction; endothelial cell; exosome; fibroblaste cardiaque; interaction cellule–cellule

DOI:  https://doi.org/10.1139/bcb-2020-0624
Front Physiol. 2021 ;12 688485

Lactate Is a Metabolic Mediator That Shapes Immune Cell Fate and Function.

Heather L Caslin, Daniel Abebayehu, Julia A Pinette, John J Ryan.

  Lactate and the associated H+ ions are still introduced in many biochemistry and general biology textbooks and courses as a metabolic by-product within fast or oxygen-independent glycolysis. However, the role of lactate as a fuel source has been well-appreciated in the field of physiology, and the role of lactate as a metabolic feedback regulator and distinct signaling molecule is beginning to gain traction in the field of immunology. We now know that while lactate and the associated H+ ions are generally immunosuppressive negative regulators, there are cell, receptor, mediator, and microenvironment-specific effects that augment T helper (Th)17, macrophage (M)2, tumor-associated macrophage, and neutrophil functions. Moreover, we are beginning to uncover how lactate and H+ utilize different transporters and signaling cascades in various immune cell types. These immunomodulatory effects may have a substantial impact in cancer, sepsis, autoimmunity, wound healing, and other immunomodulatory conditions with elevated lactate levels. In this article, we summarize the known effects of lactate and H+ on immune cells to hypothesize potential explanations for the divergent inflammatory vs. anti-inflammatory effects.

Keywords:  M2; Th17; immune; immunometabolism; immunosuppression; inflammation; lactate; lactic acid

DOI:  https://doi.org/10.3389/fphys.2021.688485
Int J Radiat Biol. 2021 Nov 02. 1-13

The importance of hypoxia in radiotherapy for the immune response, metastatic potential and FLASH-RT.

Eui Jung Moon, Kristoffer Petersson, Monica M Olcina.

   PURPOSE: Hypoxia (low oxygen) is a common feature of solid tumors that has been intensely studied for more than six decades. Here we review the importance of hypoxia to radiotherapy with a particular focus on the contribution of hypoxia to immune responses, metastatic potential and FLASH radiotherapy, active areas of research by leading women in the field.
CONCLUSION: Although hypoxia-driven metastasis and immunosuppression can negatively impact clinical outcome, understanding these processes can also provide tumor-specific vulnerabilities that may be therapeutically exploited. The different oxygen tensions present in tumors and normal tissues may underpin the beneficial FLASH sparing effect seen in normal tissue and represents a perfect example of advances in the field that can leverage tumor hypoxia to improve future radiotherapy treatments.

Keywords:  FLASH; cancer; immune system; metastasis; tumor microenvironment; ultra-high dose rate; women in research

DOI:  https://doi.org/10.1080/09553002.2021.1988178
Mol Cancer Res. 2021 Nov 02. pii: molcanres.0702.2021. [Epub ahead of print]

PERK, Beyond an Unfolded Protein Response Sensor in Estrogen-induced Apoptosis in Endocrine-Resistant Breast Cancer.

Ping Fan, V Craig Jordan.

The discovery of 17β-estradiol (E2)-induced apoptosis has clinical relevance. Mechanistically, E2 over activates nuclear estrogen receptor α (ERα) that results in stress responses. The unfolded protein response (UPR) is initiated by E2 in the endoplasmic reticulum after hours of treatment in endocrine-resistant breast cancer cells, thereby activating three UPR sensors-PRK-like endoplasmic reticulum kinase (PERK), inositol-requiring enzyme 1α (IRE1α), and activating transcription factor 6 (ATF6) with different functions. Specifically, PERK plays a critical role in induction of apoptosis while IRE1α and ATF6 are involved in the endoplasmic reticulum stress-associated degradation (ERAD) of PI3K/Akt/mTOR pathways. In addition to attenuating protein translation, PERK increases the DNA-binding activity of nuclear factor-κB (NF-κB) and subsequent tumor necrosis factor α (TNFα) expression. Additionally, PERK communicates with the mitochondria to regulate oxidative stress at mitochondria-associated endoplasmic reticulum membranes (MAMs). Furthermore, PERK is a component enriched in MAMs that interacts with multifunctional MAM-tethering proteins and integrally modulates the exchange of metabolites such as lipids, reactive oxygen species (ROS), and Ca2+ at contact sites. MAMs are also critical sites for the initiation of autophagy to remove defective organelles and misfolded proteins through specific regulatory proteins. Thus, PERK conveys signals from nucleus to these membrane-structured organelles that form an interconnected network to regulate E2-induced apoptosis. Herein, we address the mechanistic progress on how PERK acts as a multifunctional molecule to commit E2 to inducing apoptosis in endocrine-resistant breast cancer.

DOI: https://doi.org/10.1158/1541-7786.MCR-21-0702
Front Oncol. 2021 ;11 751086

A Forgotten Corner in Cancer Immunotherapy: The Role of Lipids.

Yang Yu, Lei Gao, Yunpeng Wang, Bo Xu, Ewetse Paul Maswikiti, Haiyuan Li, Peng Zheng, Pengxian Tao, Lin Xiang, Baohong Gu, Alexandra Lucas, Hao Chen.

  In the past decade, cancer immunotherapy has achieved great success owing to the unravelling of unknown molecular forces in cancer immunity. However, it is critical that we address the limitations of current immunotherapy, including immune-related adverse events and drug resistance, and further enhance current immunotherapy. Lipids are reported to play important roles in modulating immune responses in cancer. Cancer cells use lipids to support their aggressive behaviour and allow immune evasion. Metabolic reprogramming of cancer cells destroys the equilibrium between lipid anabolism and catabolism, resulting in lipid accumulation within the tumour microenvironment (TME). Consequently, ubiquitous lipids, mainly fatty acids, within the TME can impact the function and phenotype of infiltrating immune cells. Determining the complex roles of lipids and their interactions with the TME will provide new insight for improving anti-tumour immune responses by targeting lipids. Herein, we present a review of recent literature that has demonstrated how lipid metabolism reprogramming occurs in cancer cells and influences cancer immunity. We also summarise the potential for lipid-based clinical translation to modify immune treatment.

Keywords:  fatty acids; immune evasion; immunotherapy; lipids; tumour microenvironment

DOI:  https://doi.org/10.3389/fonc.2021.751086
Cytokine Growth Factor Rev. 2021 Oct 23. pii: S1359-6101(21)00078-2. [Epub ahead of print]

Pro-angiogenic activity and vasculogenic mimicry in the tumor microenvironment by leptin in cancer.

Ana K Herrera-Vargas, Eduardo García-Rodríguez, Monserrat Olea-Flores, Miguel A Mendoza-Catalán, Eugenia Flores-Alfaro, Napoleón Navarro-Tito.

  The acquired ability to induce the formation of a functional vasculature is a hallmark of cancer. Blood vessels in tumors are formed through various mechanisms, among the most important in cancer biology, angiogenesis, and vasculogenic mimicry have been described. Leptin is one of the main adipokines secreted by adipocytes in normal breast tissue and the tumor microenvironment. Here, we provide information on the relationship between leptin and the development of angiogenesis and vasculogenic mimicry in different types of cancer. Here, we report that leptin activates different pathways such as JAK-STAT3, MAPK/ERK, PKC, JNK, p38, and PI3K-Akt to induce the expression of various angiogenic factors and vasculogenic mimicry. In vivo models, leptin induces blood vessel formation through the PI3K-Akt-mTOR pathway. Interestingly, the relationship between leptin and vasculogenic mimicry was more significant in breast cancer. The information obtained suggests that leptin could be playing an essential role in tumor survival and metastasis through the induction of vascular mechanisms such as angiogenesis and vasculogenic mimicry; thus, leptin-induced pathways could be suggested as a promising therapeutic target.

Keywords:  Angiogenesis; Cancer; Leptin; Tumor microenvironment; Vasculogenic mimicry

DOI:  https://doi.org/10.1016/j.cytogfr.2021.10.006
Anticancer Res. 2021 Nov;41(11): 5469-5475

Tumor PD-L1 and VEGF Expression, and CD8 T Cell Infiltration Predict Clinical Response to Immune Checkpoint Inhibitors in Non-small Cell Lung Cancer.

Yuji Nojima, Katsuhiko Shimizu, Shinsuke Saisho, A I Maeda, Takeshi Kurosaki, Koji Kurose, Toru Oga, Mikio Oka, Masao Nakata.

   BACKGROUND/AIM: We evaluated the efficacy of "the tumor immune microenvironment (TIME) classification" for predicting clinical response to immune checkpoint inhibitors (ICIs) in patients with non-small cell lung cancer (NSCLC). In addition, we aimed to evaluate the "modified TIME classification", which adds the vascular endothelial growth factor (VEGF) status to TIME.
MATERIALS AND METHODS: Programmed cell death receptor ligand-1 (PD-L1), CD8 T cell tumor-infiltrating lymphocytes (CD8+TILs) count and VEGF expression analyses were performed using immuno - histochemistry in 44 patients who had undergone ICI monotherapy.
RESULTS: Regarding TIME classification, type-I (PD-L1 high and CD8+TILs high) had a significantly higher response than the other types. Using the modified TIME classification, type-IA (PD-L1 high, CD8+TILs high, and VEGF low) had a significantly higher response than the other types.
CONCLUSION: The modified TIME classification, which adds tumor VEGF expression to "the TIME classification", could be useful in predicting clinical response to ICI monotherapy.

Keywords:  Tumor immune microenvironment; biomarker; immune checkpoint inhibitor; non-small cell lung cancer; vascular endothelial growth factor

DOI:  https://doi.org/10.21873/anticanres.15359
Lung. 2021 Nov 01.

β2-Adrenoceptor Activation Stimulates IL-6 Production via PKA, ERK1/2, Src, and Beta-Arrestin2 Signaling Pathways in Human Bronchial Epithelia.

Rui-Gang Zhang, Ya Niu, Ke-Wu Pan, Hao Pang, Chun-Ling Chen, Chung-Yin Yip, Wing-Hung Ko.

   OBJECTIVE: β2-Adrenoceptor agonists are widely used to treat asthma because of their bronchial-dilation effects. We previously reported that isoprenaline, via the apical and basolateral β2-adrenoceptor, induced Cl- secretion by activating cyclic AMP (cAMP)-dependent pathways in human bronchial epithelia. Despite these results, whether and how the β2-adrenoceptor-mediated cAMP-dependent pathway contributes to pro-inflammatory cytokine release in human bronchial epithelia remains poorly understood.
METHODS: We investigated β2-adrenoceptor-mediated signaling pathways involved in the production of two pro-inflammatory cytokines, interleukin (IL)-6 and IL-8, in 16HBE14o- human bronchial epithelia. The effects of isoprenaline or formoterol were assessed in the presence of protein kinase A (PKA), exchange protein directly activated by cAMP (EPAC), Src, and extracellular signal-regulated protein kinase (ERK)1/2 inhibitors. The involvement of β-arrestin2 was examined using siRNA knockdown.
RESULTS: Isoprenaline and formoterol (both β2 agonists) induced IL-6, but not IL-8, release, which could be inhibited by ICI 118,551 (β2 antagonist). The PKA-specific inhibitor, H89, partially inhibited IL-6 release. Another intracellular cAMP receptor, EPAC, was not involved in IL-6 release. Isoprenaline-mediated IL-6 secretion was attenuated by dasatinib, a Src inhibitor, and PD98059, an ERK1/2 inhibitor. Isoprenaline treatment also led to ERK1/2 phosphorylation. In addition, knockdown of β-arrestin2 by siRNA specifically suppressed cytokine release when a high concentration of isoprenaline (1 mM) was used.
CONCLUSION: Our results suggest that activation of the β2-adrenoceptor in 16HBE14o- cells stimulated the PKA/Src/ERK1/2 and/or β-arrestin2 signaling pathways, leading to IL-6 release. Therefore, our data reveal that β2-adrenoceptor signaling plays a role in the immune regulation of human airway epithelia.

Keywords:  Bronchial epithelia; ERK1/2; IL-6; PKA; β-Arrestin2; β2-Adrenoceptor

DOI:  https://doi.org/10.1007/s00408-021-00484-0
Biofactors. 2021 Nov 01.

Targeting lactate metabolism and glycolytic pathways in the tumor microenvironment by natural products: A promising strategy in combating cancer.

Leila Kooshki, Parisa Mahdavi, Sajad Fakhri, Esra Küpeli Akkol, Haroon Khan.

  Anticancer drugs are not purely effective because of their toxicity, side effects, high cost, inaccessibility, and associated resistance. On the other hand, cancer is a complex public health problem that could intelligently adopt different signaling pathways and alter the body's metabolism to escape from the immune system. One of the cancer strategies to metastasize is modifying pH in the tumor microenvironment, ranging between 6.5 and 6.9. As a powerful determiner, lactate is responsible for this acidosis. It is involved in immune stimulation, including innate and adaptive immunity, apoptotic-related factors (Bax/Bcl-2, caspase), and glycolysis pathways (e.g., GLUT-1, PKM2, PFK, HK2, MCT-1, and LDH). Lactate metabolism, in turn, is interconnected with several dysregulated signaling mediators, including PI3K/Akt/mTOR, AMPK, NF-κB, Nrf2, JAK/STAT, and HIF-1α. Because of lactate's emerging and critical role, targeting lactate production and its transporters is important for preventing and managing tumorigenesis. Hence, exploring and developing novel promising anticancer agents to minimize human cancers is urgent. Based on numerous studies, natural secondary metabolites as multi-target alternative compounds with health-promoting properties possess more high effectiveness and low side effects than conventional agents. Besides, the mechanism of multi-targeted natural sources is related to lactate production and cancer-associated cross-talked factors. This review focuses on targeting the lactate metabolism/transporters, and lactate-associated mediators, including glycolytic pathways. Besides, interconnected mediators to lactate metabolism are also targeted by natural products. Accordingly, plant-derived secondary metabolites are introduced as alternative therapies in combating cancer through modulating lactate metabolism and glycolytic pathways.

Keywords:  cancer; glycolysis; lactate; natural products; therapeutic target; tumor microenvironment

DOI:  https://doi.org/10.1002/biof.1799
J Cachexia Sarcopenia Muscle. 2021 Nov 06.

Activation of Akt-mTORC1 signalling reverts cancer-dependent muscle wasting.

Alessia Geremia, Roberta Sartori, Martina Baraldo, Leonardo Nogara, Valeria Balmaceda, Georgia Ana Dumitras, Stefano Ciciliot, Marco Scalabrin, Hendrik Nolte, Bert Blaauw.

   BACKGROUND: Cancer-related muscle wasting occurs in most cancer patients. An important regulator of adult muscle mass and function is the Akt-mTORC1 pathway. While Akt-mTORC1 signalling is important for adult muscle homeostasis, it is also a major target of numerous cancer treatments. Which role Akt-mTORC1 signalling plays during cancer cachexia in muscle is currently not known. Here, we aimed to determine how activation or inactivation of the pathway affects skeletal muscle during cancer cachexia.
METHODS: We used inducible, muscle-specific Raptor ko (mTORC1) mice to determine the effect of reduced mTOR signalling during cancer cachexia. On the contrary, in order to understand if skeletal muscles maintain their anabolic capacity and if activation of Akt-mTORC1 signalling can reverse cancer cachexia, we generated mice in which we can inducibly activate Akt specifically in skeletal muscles.
RESULTS: We found that mTORC1 signalling is impaired during cancer cachexia, using the Lewis lung carcinoma and C26 colon cancer model, and is accompanied by a reduction in protein synthesis rates of 57% (P < 0.01). Further reduction of mTOR signalling, as seen in Raptor ko animals, leads to a 1.5-fold increase in autophagic flux (P > 0.001), but does not further increase muscle wasting. On the other hand, activation of Akt-mTORC1 signalling in already cachectic animals completely reverses the 15-20% loss in muscle mass and force (P < 0.001). Interestingly, Akt activation only in skeletal muscle completely normalizes the transcriptional deregulation observed in cachectic muscle, despite having no effect on tumour size or spleen mass. In addition to stimulating muscle growth, it is also sufficient to prevent the increase in protein degradation normally observed in muscles from tumour-bearing animals.
CONCLUSIONS: Here, we show that activation of Akt-mTORC1 signalling is sufficient to completely revert cancer-dependent muscle wasting. Intriguingly, these results show that skeletal muscle maintains its anabolic capacities also during cancer cachexia, possibly giving a rationale behind some of the beneficial effects observed in exercise in cancer patients.

Keywords:  Akt; Cancer cachexia; Muscle growth; Raptor; Skeletal muscle force; mTOR

DOI:  https://doi.org/10.1002/jcsm.12854