bims-stacyt 2020-06-28 papers

bims-stacyt

Biomed News

on Metabolism and the paracrine crosstalk between cancer and the organism

Issue of 2020–06–28
ten papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge

The Immune Consequences of Lactate in the Tumor Microenvironment.
Metabolism in the Tumor Microenvironment.
Fatty Acid Mediators in the Tumor Microenvironment.
Secretome of Hypoxic Endothelial Cells Stimulates Bone Marrow-Derived Mesenchymal Stem Cells to Enhance Alternative Activation of Macrophages.
Exosomes derived from endoplasmic reticulum-stressed liver cancer cells enhance the expression of cytokines in macrophages via the STAT3 signaling pathway.
Ischemic Preconditioning Upregulates Decoy Receptors to Protect SH-SY5Y Cells from OGD Induced Cellular Damage by Inhibiting TRAIL Pathway and Agitating PI3K/Akt Pathway.
Metformin suppresses HIF-1α expression in cancer-associated fibroblasts to prevent tumor-stromal cross talk in breast cancer.
Metabolic modulation via mTOR pathway and anti-angiogenesis remodels tumor microenvironment using PD-L1-targeting codelivery.
Recent advances in the role of interleukin-6 in health and disease.
Role of Altered Metabolic Microenvironment in Osteolytic Metastasis.

Adv Exp Med Biol. 2020 ;1259 113-124

The Immune Consequences of Lactate in the Tumor Microenvironment.

Cathal Harmon, Cliona O'Farrelly, Mark W Robinson.

  The tumor microenvironment consists of complex and dynamic networks of cytokines, growth factors, and metabolic products. These contribute to significant alterations in tissue architecture, cell growth, immune cell phenotype, and function. Increased glycolytic flux is commonly observed in solid tumors and is associated with significant changes in metabolites, generating high levels of lactate. While elevated glycolytic flux is a characteristic metabolic adaption of tumor cells, glycolysis is also a key metabolic program utilized by a variety of inflammatory immune cells. As such lactate and the pH changes associated with lactate transport affect not only tumor cells but also immune cells. Here we provide an overview of lactate metabolic pathways and the effects lactate has on tumor growth and immune cell function. This knowledge provides opportunities for synergistic therapeutic approaches that combine metabolic drugs, which limit tumor growth and support immune cell function, together with immunotherapies to enhance tumor eradication.

Keywords:  Anti-tumor immunity; Biosynthesis; Glycolysis; Immunotherapy; Lactate; Lactic acid; MCT; Macrophages; Metabolic therapies; Metabolism; NK cells; T cells; Tumor microenvironment; Warburg; pH

DOI:  https://doi.org/10.1007/978-3-030-43093-1_7
Adv Exp Med Biol. 2020 ;1263 1-11

Metabolism in the Tumor Microenvironment.

Francesca Montenegro, Stefano Indraccolo.

  From a general perspective, in the context of solid tumors, we can distinguish metabolic alterations of cancer cells from those of the stroma. These two components interact with each other and with the extracellular matrix (ECM), and these interactions can take the form of either metabolic competition or metabolic symbiosis. The aim of this chapter is to overview the canonical metabolic alterations of tumor and stroma cells and to present specific examples of metabolic competition and symbiosis. We will also discuss the complexity and plasticity of metabolism, which pose indeed a serious threat to our ability to target selective metabolic features of tumor microenvironment with drugs. Finally, we will highlight some limitations of state-of-the-art techniques used to study tumor metabolism and propose some innovative solutions to investigate the clinical relevance of metabolic alterations for patient management and treatment.

Keywords:  Angiogenesis; Glucose; Glutamine; Glycolysis; Hypoxia; Immune cell; Lactate; Lipids; Metabolic competition; Metabolic symbiosis; Metabolism; Microenvironment; OXPHOS; Stroma; Tumor

DOI:  https://doi.org/10.1007/978-3-030-44518-8_1
Adv Exp Med Biol. 2020 ;1259 125-153

Fatty Acid Mediators in the Tumor Microenvironment.

Saraswoti Khadge, John Graham Sharp, Geoffrey M Thiele, Timothy R McGuire, James E Talmadge.

  Patients with cancer frequently overexpress inflammatory cytokines with an associated neutrophilia both of which may be downregulated by diets with high omega-3 polyunsaturated fatty acids (ω-3 PUFA). The anti-inflammatory activity of dietary ω-3 PUFA has been suggested to have anticancer properties and to improve survival of cancer patients. Currently, the majority of dietary research efforts do not differentiate between obesity and dietary fatty acid consumption as mediators of inflammatory cell expansion and tumor microenvironmental infiltration, initiation, and progression. In this chapter, we discuss the relationships between dietary lipids, inflammation, neoplasia and strategies to regulate these relationships. We posit that dietary composition, notably the ratio of ω-3 vs. ω-6 PUFA, regulates tumor initiation and progression and the frequency and sites of metastasis that, together, impact overall survival (OS). We focus on three broad topics: first, the role of dietary lipids in chronic inflammation and tumor initiation, progression, and regression; second, lipid mediators linking inflammation and cancer; and third, dietary lipid regulation of murine and human tumor initiation, progression, and metastasis.

Keywords:  Cancer; Diet; Inflammation; Lipoxygenases; Metastasis; Myeloid-derived suppressor cells; Myeloplasia; Neutrophils; Omega 3 polyunsaturated fatty acids; Prostaglandins; Tumor progression

DOI:  https://doi.org/10.1007/978-3-030-43093-1_8
Int J Mol Sci. 2020 Jun 21. pii: E4409. [Epub ahead of print]21(12):

Secretome of Hypoxic Endothelial Cells Stimulates Bone Marrow-Derived Mesenchymal Stem Cells to Enhance Alternative Activation of Macrophages.

Kang-Ju Chou, Chih-Yang Hsu, Chien-Wei Huang, Hsin-Yu Chen, Shih-Hsiang Ou, Chien-Liang Chen, Po-Tsang Lee, Hua-Chang Fang.

  We intended to explore the cellular interaction between mesenchymal stem cells (MSCs) and injured endothelial cells leading to macrophage alternative polarization in healing kidney ischemic reperfusion injury. In vivo, the amounts of recruited macrophages were significantly mitigated by MSCs in the injured tissues, especially in the group using hematopoietic cell E- and L-selectin ligand (HCELL)-positive MSCs. Compared to controls, MSCs also enhanced expression of CD206 and CD163, which was further enhanced by HCELL expression. In vitro, analysis of cytokines involving macrophage polarization showed IL-13 rather than IL-4 from MSCs agreed with expression of macrophage CD206 in the presence of hypoxic endothelial cells. Among them, HCELL-positive MSCs in contact with hypoxic endothelial cells produced the greatest response, which were reduced without HCELL or using a transwell to prevent cell contact. With blockade of the respective cytokine, downregulated MSCs secretion of IL-13 and CD206 expression were observed using inhibitors of IFN-γ and TNF-α, but not using those of TGF-β and NO. With IFN-γ and TNF-α, MSCs IL-13 secretion and CD206 expression were upregulated. In conclusion, hypoxia induces endothelial cells producing multiple cytokines. Among them, IFN-γ and TNF-α that stimulate MSCs to secrete IL-13 but not IL-4, leading to alternative polarization.

Keywords:  alternative macrophage polarization; hematopoietic cell E- and L-selectin ligand; hypoxic endothelial cells; mesenchymal stem cells

DOI:  https://doi.org/10.3390/ijms21124409
Oncol Lett. 2020 Jul;20(1): 589-600

Exosomes derived from endoplasmic reticulum-stressed liver cancer cells enhance the expression of cytokines in macrophages via the STAT3 signaling pathway.

Chengqun He, Wei Hua, Jiatao Liu, Lulu Fan, Hua Wang, Guoping Sun.

  Previous studies have shown that endoplasmic reticulum (ER) stress serves an important role in shaping the immunosuppressive microenvironment by modulating resident immune cells. However, the communication between ER-stressed tumor cells and immune cells is not fully understood. Exosomes have been reported to play a vital role in intercellular communication. Therefore, in order to investigate the role of ER stress-related exosomes in liver cancer cells mediated macrophage function remodeling, immunohistochemical analysis, western-blotting immunofluorescence and cytokine bead array analyses were performed. The results demonstrated that glucose-regulated protein 78 (GRP78) expression was upregulated in human liver cancer tissue. Moreover, 69.09% of GRP78-positive liver cancer tissues possessed macrophages expressing CD68+ (r=0.55; P<0.001). In addition to these CD68+ macrophages, interleukin (IL)-10 and IL-6 expression levels were increased in liver cancer tissues. It was also demonstrated that exosomes released by ER-stressed HepG2 cells significantly enhanced the expression levels of several cytokines, including IL-6, monocyte chemotactic protein-1, IL-10 and tumor necrosis factor-α in macrophages. Furthermore, incubation of cells with ER stress-associated exosomes resulted inactivation of the Janus kinase 2/STAT3 pathway, and inhibition of STAT3 using S3I-201 in RAW264.7 cells significantly reduced cytokine production. Collectively, the present study identified a novel function of ER stress-associated exosomes in mediating macrophage cytokine secretion in the liver cancer microenvironment, and also indicated the potential of treating liver cancer via an ER stress-exosomal-STAT3 pathway.

Keywords:  endoplasmic reticulum stress; exosome; inflammation; liver cancer; macrophage

DOI:  https://doi.org/10.3892/ol.2020.11609
Mol Neurobiol. 2020 Jun 20.

Ischemic Preconditioning Upregulates Decoy Receptors to Protect SH-SY5Y Cells from OGD Induced Cellular Damage by Inhibiting TRAIL Pathway and Agitating PI3K/Akt Pathway.

Wei Jin, Wei Xu, Xiaoxiao Zhang, Chuan-Cheng Ren.

  As ischemic preconditioning (IPC) represents a potential therapy against cerebral ischemia, the purpose of the present study is to explore the molecular mechanisms of ischemic preconditioning induced cerebral protective effect. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a member of the tumor necrosis factor superfamily, which induces apoptosis through binding to its death receptors (DR4 and DR5). When TRAIL binds to decoy receptors (DcR1 and DcR2), as DcRs lack intact cytoplasmic death domain, TRAIL fails to induce neuronal apoptosis. In the present study, we demonstrated that ischemic preconditioning upregulated DcR1 and DcR2, which subsequently inhibited oxygen glucose deprivation-induced cellular apoptosis. Then, we investigated the protective molecular mechanism of DcRs after ischemic preconditioning treatment. Results showed that DcR1 could competitively bind to TRAIL and partially inhibit TRAIL-induced cellular apoptosis. On the other hand, DcR2 could disturb DRs-associated death-inducing signaling complex formation (DISC), which further inhibited capase-8 activation. Besides, we also found that ischemic preconditioning activated IPC-induced Akt phosphorylation via regulating DcR2 level. Thus, ischemic preconditioning upregulated decoy receptors, which protected cells from oxygen glucose deprivation-induced cellular damage by inhibiting TRAIL-induced apoptosis and agitating PI3K/Akt pathway. Our data complemented the knowledge of neuroprotective mechanism of ischemic preconditioning and provided new evidence for supporting its clinical application.

Keywords:  Decoy receptor; Ischemic preconditioning; Neuronal apoptosis; PI3K/Akt pathway; TRAIL

DOI:  https://doi.org/10.1007/s12035-020-01978-3
FASEB J. 2020 Jun 27.

Metformin suppresses HIF-1α expression in cancer-associated fibroblasts to prevent tumor-stromal cross talk in breast cancer.

Shan Shao, Lin Zhao, Gaili An, Lingxiao Zhang, Xin Jing, Minna Luo, Wei Li, Du Meng, Qian Ning, Xinhan Zhao, Jianjun Lei.

  The tumor microenvironment (TME) is a crucial factor in cancer progression. In breast cancer, cancer-associated fibroblasts (CAFs) and the derived stromal components have been recognized as comprising the majority of the pathological structure of the TME. In this study, we show that metformin (Met), a diabetes drug, transforms CAFs in the TME. Met disrupts tumor-stromal cross talk by preventing breast cancer cell transforming growth factor-β (TGF-β) signaling and the production of stromal-derived factor-1 (SDF-1) and interleukin-8 (IL-8) by CAFs. The suppression of bidirectional signaling between tumor cells and CAFs by Met is attributed to increased phospho-AMP kinase (p-AMPK) levels. By upregulating p-AMPK in CAFs, Met induces prolyl hydroxylases (PHDs), leading to the degradation of hypoxia-inducible factor-1α (HIF-1α) in CAFs. Moreover, interruption of HIF-1α-driven SDF-1 signaling in CAFs by Met leads to decreased breast cancer cell invasion. These findings suggest that Met may be used to target tumor-promoting signaling between CAFs and breast cancer cells in the TME.

Keywords:  cancer-associated fibroblasts; hypoxia-inducible factor-1α; metformin; phospho-AMPK; tumor microenvironment

DOI:  https://doi.org/10.1096/fj.202000951RR
Biomaterials. 2020 Jun 12. pii: S0142-9612(20)30433-6. [Epub ahead of print]255 120187

Metabolic modulation via mTOR pathway and anti-angiogenesis remodels tumor microenvironment using PD-L1-targeting codelivery.

Binfan Chen, Ang Gao, Bin Tu, Yonghui Wang, Xiaolu Yu, Yingshu Wang, Yanfeng Xiu, Bing Wang, Yakun Wan, Yongzhuo Huang.

  Tumor microenvironment (TME) closely affects cancer progression by promoting cancer cell survival and proliferation, drug resistance, metastasis, and immunosuppression as well. Remodeling TME is a promising therapeutic strategy for anticancer. mTOR signaling is an essential regulator for cellular metabolism and tumor-associated macrophages (TAMs) repolarization. There is an integrated crosstalk among mTOR/metabolism/immunity. Angiogenesis can also regulate metabolism and immunity. Based on these, a potential therapeutic avenue was developed by targeting mTOR and angiogenesis to remodel tumor immune microenvironment (TIME). A dual-targeting delivery liposomal system was designed with dual-modification of PD-L1 nanobody and mannose ligands for co-delivering an mTOR inhibitor (rapamycin) and an anti-angiogenic drug (regorafenib). The liposomes were able to target both TAMs and cancer cells that overexpressed PD-L1 and mannose receptors. The liposomes efficiently reduced glycolysis, repolarized TAMs, inhibited angiogenesis, reprogrammed immune cells, and consequently arrested tumor growth.

Keywords:  Angiogenesis; Glycolysis; Liposome; Tumor immune microenvironment; Tumor-associated macrophage; mTOR

DOI:  https://doi.org/10.1016/j.biomaterials.2020.120187
Curr Opin Pharmacol. 2020 Jun 18. pii: S1471-4892(20)30019-9. [Epub ahead of print]52 47-51

Recent advances in the role of interleukin-6 in health and disease.

Willem T Peppler, Logan K Townsend, David C Wright.

Interleukin-6 (IL-6) is a pleotropic cytokine, and in this review, we highlight recent studies focusing on the role of IL-6 in health and disease. IL-6 is known as an exercise-inducible myokine, and in rodents it was identified that a lactate-dependent increase in protease activity mediates IL-6 release from skeletal muscle, which acts in both an autocrine and paracrine roles. In humans, a series of publications observed that blocking IL-6 during exercise training prevented beneficial adaptations, such as reductions in visceral and epicardial fat mass. Independent of exercise, IL-6 impacts postprandial physiology, as demonstrated by a slowing of gastric emptying rate and improving glucose homeostasis. Finally, an engineered cytokine harnessing the biology of IL-6, termed IC7Fc, was found to have beneficial impacts on numerous health outcomes. Together, these recent advances indicate that IL-6 has a multifaceted, and perhaps beneficial, role in health and disease.

DOI: https://doi.org/10.1016/j.coph.2020.04.010
Front Cell Dev Biol. 2020 ;8 435

Role of Altered Metabolic Microenvironment in Osteolytic Metastasis.

Kerstin Tiedemann, Osama Hussein, Svetlana V Komarova.

  Metastatic bone disease is generally incurable and leads to pathological fractures, pain, hypercalcemia, spinal cord compression and decreased mobility. The skeleton is the major site of bone metastases from solid cancers, including breast and prostate carcinoma. Bone metastasis is facilitated by activation of bone-resorbing osteoclasts, terminally differentiated multinucleated cells formed by fusion from monocytic precursors. Cancer cells are known to produce specific factors that stimulate osteoclast differentiation and function. Of interest, cancer cells are also known to alter their own bioenergetics increasing the use of glycolysis for their survival and function. Such change in energy utilization by cancer cells would result in altered levels of cell-permeable metabolites, including glucose, lactate, and pyruvate. Osteoclast resorption is energy-expensive, and we have previously demonstrated that during differentiation osteoclasts actively adapt to their bioenergetics microenvironment. We hypothesize that altered bioenergetics state of cancer cells will also modify the bioenergetics substrate availability for the tissue-resident bone cells, potentially creating a favorable milieu for pathological osteolysis. The goals of this review are to analyze how metastasizing cancer cells change the availability of energy substrates in bone microenvironment; and to assess how the altered bioenergetics may affect osteoclast differentiation and activity.

Keywords:  bioenergetics; bone microenvironment; cancer; metabolic sensors; metabolism; osteoclast; osteolysis

DOI:  https://doi.org/10.3389/fcell.2020.00435