bims-stacyt 2021-03-14 papers

bims-stacyt

Biomed News

on Metabolism and the paracrine crosstalk between cancer and the organism

Issue of 2021–03–14
eleven papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge

Exosomal HMGB1 derived from hypoxia-conditioned bone marrow mesenchymal stem cells increases angiogenesis via the JNK/HIF-1α pathway.
MAPKAP Kinase-2 Drives Expression of Angiogenic Factors by Tumor-Associated Macrophages in a Model of Inflammation-Induced Colon Cancer.
G-CSF in tumors: Aggressiveness, tumor microenvironment and immune cell regulation.
High extracellular ATP levels released through pannexin-1 channels mediate inflammation and insulin resistance in skeletal muscle fibres of diet-induced obese mice.
Nano formulated Resveratrol inhibits metastasis and angiogenesis by reducing inflammatory cytokines in oral cancer cells by targeting tumor associated macrophages.
Remote Limb Ischemic Postconditioning Protects against Ischemic Stroke via Modulating Microglia/Macrophage Polarization in Mice.
Dynamic Immune/Inflammation Precision Medicine: The Good and the Bad Inflammation in Infection and Cancer.
Dynamic roles of inflammasomes in inflammatory tumor microenvironment.
The roles of metastasis-related proteins in the development of giant cell tumor of bone, osteosarcoma and Ewing's sarcoma.
Autophagy-Mediated Exosomes as Immunomodulators of Natural Killer Cells in Pancreatic Cancer Microenvironment.
High gene expression of estrogen and progesterone receptors is associated with decreased t cell infiltration in patients with NSCLC.

FEBS Open Bio. 2021 Mar 12.

Exosomal HMGB1 derived from hypoxia-conditioned bone marrow mesenchymal stem cells increases angiogenesis via the JNK/HIF-1α pathway.

Wenling Gao, Ronghan He, Jianhua Ren, Wenhui Zhang, Kun Wang, Lei Zhu, Tangzhao Liang.

  Mesenchymal stem cells (MSCs) have been described to induce angiogenesis in various tissues and have been utilized for the development of novel cell-based therapies. Increasing evidence suggests that MSCs execute their paracrine function via the secretion of exosomes, especially under hypoxic conditions. However, the mechanisms by which MSCs-derived exosomes secreted under hypoxia enhance angiogenesis still remain unclear. In order to study exosome physiology under hypoxic or normoxic conditions we isolated exosomes from bone marrow mesenchymal stem cells (BMSCs). Furthermore, we detected the uptake of exosomes by HUVEC cells by immunofluorescence staining. Additionally, we determined the effects of exosomes on cell viability, migration and tube formation in HUVECs by CCK-8, migration and tube formation assays, respectively. We examined the expression of key proteins related to exosome induced angiogenesis by BMSCs cultured under hypoxic conditions by western blot. Exosomes released by BMSCs cultured under hypoxic conditions enhanced cell proliferation, migration and angiogenesis of HUVEC cells. Hypoxia induced the expression of HMGB1 in BMSC-derived exosomes, and silencing of HMGB1 abolished the angiogenic effect in HUVEC cells. Furthermore, exosomal HMGB1 activated the JNK signaling pathway and induced HIF-1α/VEGF expression, consequently enhancing angiogenesis in HUVECs. Our data reveal that exosomal HMGB1 promotes angiogenesis via JNK/HIF-1α signaling. Therefore, BMSC exosomes derived under hypoxia may have potential for development of novel treatment strategies for angiogenesis-related diseases.

Keywords:  Angiogenesis; HMGB1; bone marrow mesenchymal stem cells; exosome; hypoxia

DOI:  https://doi.org/10.1002/2211-5463.13142
Front Immunol. 2020 ;11 607891

MAPKAP Kinase-2 Drives Expression of Angiogenic Factors by Tumor-Associated Macrophages in a Model of Inflammation-Induced Colon Cancer.

Lucia Suarez-Lopez, Yi Wen Kong, Ganapathy Sriram, Jesse C Patterson, Samantha Rosenberg, Sandra Morandell, Kevin M Haigis, Michael B Yaffe.

  Chronic inflammation increases the risk for colorectal cancer through a variety of mechanisms involving the tumor microenvironment. MAPK-activated protein kinase 2 (MK2), a major effector of the p38 MAPK stress and DNA damage response signaling pathway, and a critical regulator of pro-inflammatory cytokine production, has been identified as a key contributor to colon tumorigenesis under conditions of chronic inflammation. We have previously described how genetic inactivation of MK2 in an inflammatory model of colon cancer results in delayed tumor progression, decreased tumor angiogenesis, and impaired macrophage differentiation into a pro-tumorigenic M2-like state. The molecular mechanism responsible for the impaired angiogenesis and tumor progression, however, has remained contentious and poorly defined. Here, using RNA expression analysis, assays of angiogenesis factors, genetic models, in vivo macrophage depletion and reconstitution of macrophage MK2 function using adoptive cell transfer, we demonstrate that MK2 activity in macrophages is necessary and sufficient for tumor angiogenesis during inflammation-induced cancer progression. We identify a critical and previously unappreciated role for MK2-dependent regulation of the well-known pro-angiogenesis factor CXCL-12/SDF-1 secreted by tumor associated-macrophages, in addition to MK2-dependent regulation of Serpin-E1/PAI-1 by several cell types within the tumor microenvironment.

Keywords:  MAPKAP kinase 2; angiogenesis; colon tumors; inflammation driven tumorigenesis; signal transduction; stress signaling; tumor associated macrophage (TAM)

DOI:  https://doi.org/10.3389/fimmu.2020.607891
Cytokine. 2021 Mar 04. pii: S1043-4666(21)00059-4. [Epub ahead of print]142 155479

G-CSF in tumors: Aggressiveness, tumor microenvironment and immune cell regulation.

Ioannis Karagiannidis, Eralda Salataj, Erika Said Abu Egal, Ellen J Beswick.

  Granulocyte colony-stimulating factor (G-CSF) is a cytokine most well-known for maturation and mobilization of bone marrow neutrophils. Although it is used therapeutically to treat chemotherapy induced neutropenia, it is also highly expressed in some tumors. Case reports suggest that tumors expressing high levels of G-CSF are aggressive, more difficult to treat, and present with poor prognosis and high mortality rates. Research on this topic suggests that G-CSF has tumor-promoting effects on both tumor cells and the tumor microenvironment. G-CSF has a direct effect on tumor cells to promote tumor stem cell longevity and overall tumor cell proliferation and migration. Additionally, it may promote pro-tumorigenic immune cell phenotypes such as M2 macrophages, myeloid-derived suppressor cells, and regulatory T cells. Overall, the literature suggests a plethora of pro-tumorigenic activity that should be balanced with the therapeutic use. In this review, we present an overview of the multiple complex roles of G-CSF and G-CSFR in tumors and their microenvironment and discuss how clinical advances and strategies may open new therapeutic avenues.

Keywords:  Colorectal cancer; G-CSF; G-CSF receptor; Immune cells; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.cyto.2021.155479
Diabetologia. 2021 Mar 12.

High extracellular ATP levels released through pannexin-1 channels mediate inflammation and insulin resistance in skeletal muscle fibres of diet-induced obese mice.

Gonzalo Jorquera, Roberto Meneses-Valdés, Giovanni Rosales-Soto, Denisse Valladares-Ide, Cristian Campos, Mónica Silva-Monasterio, Paola Llanos, Gonzalo Cruz, Enrique Jaimovich, Mariana Casas.

   AIMS/HYPOTHESIS: Skeletal muscle is a key target organ for insulin's actions and is the main regulator of blood glucose. In obese individuals and animal models, there is a chronic low-grade inflammatory state affecting highly metabolic organs, leading to insulin resistance. We have described that adult skeletal muscle fibres can release ATP to the extracellular medium through pannexin-1 (PANX1) channels. Besides, it is known that high extracellular ATP concentrations can act as an inflammatory signal. Here, we propose that skeletal muscle fibres from obese mice release high levels of ATP, through PANX1 channels, promoting inflammation and insulin resistance in muscle cells.
METHODS: C57BL/6J mice were fed with normal control diet (NCD) or high-fat diet (HFD) for 8 weeks. Muscle fibres were isolated from flexor digitorum brevis (FDB) muscle. PANX1-knockdown FDB fibres were obtained by in vivo electroporation of a short hairpin RNA Panx1 plasmid. We analysed extracellular ATP levels in a luciferin/luciferase assay. Gene expression was studied with quantitative real-time PCR (qPCR). Protein levels were evaluated by immunoblots, ELISA and immunofluorescence. Insulin sensitivity was analysed in a 2-NBDG (fluorescent glucose analogue) uptake assay, immunoblots and IPGTT.
RESULTS: HFD-fed mice showed significant weight gain and insulin resistance compared with NCD-fed mice. IL-6, IL-1β and TNF-α protein levels were increased in FDB muscle from obese mice. We observed high levels of extracellular ATP in muscle fibres from obese mice (197 ± 55 pmol ATP/μg RNA) compared with controls (32 ± 10 pmol ATP/μg RNA). ATP release in obese mice fibres was reduced by application of 100 μmol/l oleamide (OLE) and 5 μmol/l carbenoxolone (CBX), both PANX1 blockers. mRNA levels of genes linked to inflammation were reduced using OLE, CBX or 2 U/ml ATPase apyrase in muscle fibres from HFD-fed mice. In fibres from mice with pannexin-1 knockdown, we observed diminished extracellular ATP levels (78 ± 10 pmol ATP/μg RNA vs 252 ± 37 pmol ATP/μg RNA in control mice) and a lower expression of inflammatory markers. Moreover, a single pulse of 300 μmol/l ATP to fibres from control mice reduced insulin-mediated 2-NBDG uptake and promoted an elevation in mRNA levels of inflammatory markers. PANX-1 protein levels were increased two- to threefold in skeletal muscle from obese mice compared with control mice. Incubation with CBX increased Akt activation and 2-NBDG uptake in HFD fibres after insulin stimulation, rescuing the insulin resistance condition. Finally, in vivo treatment of HFD-fed mice with CBX (i.p. injection of 10 mg/kg each day) for 14 days, compared with PBS, reduced extracellular ATP levels in skeletal muscle fibres (51 ± 10 pmol ATP/μg RNA vs 222 ± 28 pmol ATP/μg RNA in PBS-treated mice), diminished inflammation and improved glycaemic management.
CONCLUSIONS/INTERPRETATION: In this work, we propose a novel mechanism for the development of inflammation and insulin resistance in the skeletal muscle of obese mice. We found that high extracellular ATP levels, released by overexpressed PANX1 channels, lead to an inflammatory state and insulin resistance in skeletal muscle fibres of obese mice.

Keywords:  Carbenoxolone; Extracellular nucleotides; High-fat diet; PANX1; Purinergic signalling; Skeletal muscle

DOI:  https://doi.org/10.1007/s00125-021-05418-2
J Nutr Biochem. 2021 Mar 08. pii: S0955-2863(21)00044-9. [Epub ahead of print] 108624

Nano formulated Resveratrol inhibits metastasis and angiogenesis by reducing inflammatory cytokines in oral cancer cells by targeting tumor associated macrophages.

Rajalaxmi Pradhan, Subhajit Chatterjee, Krushna Chandra Hembram, Chinmayee Sethy, Mahitosh Mandal, Chanakya Nath Kundu.

  Tumor associated macrophages (TAMs) in the tumor microenvironment (TME) secrete multiple cytokines, which regulate cancer cells growth and invasiveness. We systematically studied the role of cytokines in the induction of cancer stem like cells (CSCs) in oral cancer cells niche and evaluated the mechanism of Resveratrol nanoparticle (Res-Nano) mediated-reduction of CSCs properties in cells. A highly M1-like macrophages-enriched conditioned medium (CM) was generated by treating fixed doses of PMA and LPS in THP-1 cells alone as well as co-cultured of H-357 plus THP-1 cells. These M1-like macrophages increased the production of cytokines (e.g. TNF-α, IL6, IL-β, etc.). A CSCs populated environment was created after addition of cytokine-enriched-CM of co-culture of H-357 and THP-1 cells to cancer cells and cytokine enriched CM of THP-1 cells to patient derived primary oral cancer cells, respectively. After incubation with CM, enhancement of stemness, angiogenic and metastatic properties of both H-357 and primary oral cancer cells were noted. Res-NP decreased the cytokines level in CSCs-enriched cells and reduced the invasion, proliferation and growth of CSCs. Representative metastatic (CD133, ALDH1, CXCR4, etc.) and angiogenic markers (MMPs, iNOS, VEGF-A, etc.) were decreased after Res-NP treatment in CSCs enriched oral cancer cells niche. It also disrupted angiogenesis, depleted nitric oxide production in fertilized chick embryos and reduced the expression of metastatic and angiogenic markers in xenograft mice model system. Thus, this study concluded that CSCs-mediated stemness is a cytokine dependent phenomena and treatment of Res-NP inhibit this process in in vitro, in vivo and ex vivo systems.

Keywords:  Angiogenesis; Cancer stem cells (CSCs); Cytokines; Macrophages; Oral cancer; Resveratrol-nanoparticle

DOI:  https://doi.org/10.1016/j.jnutbio.2021.108624
J Immunol Res. 2021 ;2021 6688053

Remote Limb Ischemic Postconditioning Protects against Ischemic Stroke via Modulating Microglia/Macrophage Polarization in Mice.

Dong Han, Jue Wang, Lulu Wen, Miao Sun, Hang Liu, Yan Gao.

Aim: The protection against ischemia/reperfusion injury mediated by remote limb ischemic postconditioning (RIPC) shows great clinical value in ischemic stroke therapy, but the particular mechanism of RIPC remains unclear.
Methods: We carried out middle cerebral artery occlusion/reperfusion (MCAO/R) surgery on C57BL/6 male mice. RIPC was generated by 10-minute occlusion followed by the same period of reperfusion of the bilateral hind limb femoral artery and repeated for 3 cycles. Infarct size and neurological score were performed to assess stroke outcomes. Ly6Chi monocytes were quantified in the blood and brain by flow cytometry. Real-time PCR, ELISA, and immunofluorescence were utilized to detect phenotype of proinflammatory M1 and anti-inflammatory M2 microglia/macrophage. Nuclear factor κB (NF-κB) and peroxisome proliferator-activated receptor γ (PPARγ) levels were detected using Western blot.
Results: At 24 and 72 h after MCAO, RIPC drastically attenuated infarct size and ameliorated the neurological deficits of mice and facilitated transmigration of Ly6Chi monocytes to the brain postischemia reperfusion. Furthermore, RIPC contributed to increased M2 and reduced M1 microglia/macrophage through inhibiting NF-κB and promoting PPARγ activation.
Conclusion: Our results reveal pharmacological effect of RIPC in promoting microglia/macrophage transferring from M1 to M2 phenotype after MCAO/R in mice, which provides theoretical support for the therapeutic effect of RIPC in ischemic stroke.

DOI: https://doi.org/10.1155/2021/6688053
Front Immunol. 2021 ;12 595722

Dynamic Immune/Inflammation Precision Medicine: The Good and the Bad Inflammation in Infection and Cancer.

Jean-François Rossi, Zhao Yang Lu, Cesare Massart, Kalle Levon.

  Normal or "good" inflammation process starts from a local cellular response against injury or any infectious agent, with the activation of neutrophils, macrophages, Langerhans cells, dendritic cells, and innate immune cells. Cytokines and chemokines are produced to amplify the local inflammatory process followed by the migration of immune cells to the regional lymph nodes where adaptive immune response is initiated. Systemic inflammation enhances the biological response to mobilize additional cells from central and peripheral immune/hematopoietic system. Local mechanisms to limit inflammation are initiated and lead to healing. During the normal inflammatory process, there is a balance between the production of inflammatory chemokines/cytokines such as Tumor Necrosis Factor (TNF)-α, interleukin (IL)-6 and IL-1 and the production of compounds that limit inflammation and have an immune suppressive effect, such as IL-10 and Transforming Factor (TGF) β. IL-6 and IL-6/soluble IL-6 Receptor (R) complex stimulate liver cells to produce inflammatory proteins, which represents the systemic inflammation response. The magnitude and the duration of the systemic inflammatory response are linked to the cause, under genetic and epigenetic control. Significant inflammation as seen in septic shock, in severe forms of infections or in certain active cancers, represents the "bad inflammation", correlated with a poor prognosis. In addition, the persistence of a chronic smoldering inflammation may lead to pathological situations which are observed in the majority of inflammatory, degenerative, dysmetabolic, or dysimmune diseases and cancer. Chronic smoldering inflammation is a cross between different pathological situations possibly linked. In addition, within the tumor microenvironment, inflammatory process results from different cellular mechanisms modulated by metabolic and vascular changes. On the contrary, a limited and balanced inflammation initiates the normal immune response, including the adaptive response which amplifies any immunotherapy, including vaccines. Immune checkpoint inhibitors and chimeric antigen receptor (CAR) T-cells are associated with cytokine release syndrome, a clinical risk leading to the use of anti-cytokine drugs. Nowadays, it is time to monitor the dynamic inflammatory process for a better immune precision medicine in both infections and cancer.

Keywords:  cancer; immune therapy; infection; inflammation; precision medicine

DOI:  https://doi.org/10.3389/fimmu.2021.595722
NPJ Precis Oncol. 2021 Mar 08. 5(1): 18

Dynamic roles of inflammasomes in inflammatory tumor microenvironment.

Jeong-Hoon Jang, Do-Hee Kim, Young-Joon Surh.

The inflammatory tumor microenvironment has been known to be closely connected to all stages of cancer development, including initiation, promotion, and progression. Systemic inflammation in the tumor microenvironment is increasingly being recognized as an important prognostic marker in cancer patients. Inflammasomes are master regulators in the first line of host defense for the initiation of innate immune responses. Inflammasomes sense pathogen-associated molecular patterns and damage-associated molecular patterns, following recruitment of immune cells into infection sites. Therefore, dysregulated expression/activation of inflammasomes is implicated in pathogenesis of diverse inflammatory disorders. Recent studies have demonstrated that inflammasomes play a vital role in regulating the development and progression of cancer. This review focuses on fate-determining roles of the inflammasomes and the principal downstream effector cytokine, IL-1β, in the tumor microenvironment.

DOI: https://doi.org/10.1038/s41698-021-00154-7
Technol Health Care. 2021 Feb 26.

The roles of metastasis-related proteins in the development of giant cell tumor of bone, osteosarcoma and Ewing's sarcoma.

Bo Dou, Tianrui Chen, Qiubo Chu, Guirong Zhang, Zhaoli Meng.

   BACKGROUND: Giant cell tumor of bone (GC), osteosarcoma (OS) and Ewing's sarcoma (ES) are three different types of bone cancer with common and specific pathology features.
OBJECTIVE: The purpose of the study was to examine the relationship and differences of the three bone tumors using clinical samples.
METHODS: Through screening the profiles of clinical samples from GC, OS and ES patients using a humanoncology array, we found 26, 25 and 15 tumorigenesis factors significantly increased in GS, OS and ES tissues compared to normal individuals. eNOS, endostatin, HIF-1α, IL-6, CCL2/MCP-1, CCL8/MCP-2, CCL7/MCP-3, Tie and VEGF directly or indirectly involve in the metastasis Therefore, expression levels of the 6 factors were further determined by Western blot.
RESULTS: The results showed levels of MCP1, MCP2, MCP3 or IL-6 in the GS, OS and ES significantly increased, and the expression levels of angiogenesis and anti-angiogenesis factors containing eNOS, endostatin, HIF-1α, Tie or VEGF were enhanced.
CONCLUSIONS: Our results suggest that eNOS, endostatin, HIF-1α, IL-6, CCL2/MCP-1, CCL8/MCP-2, CCL7/MCP-3, Tie and VEGF may play important roles in tumorigenesis, reveal the expression differences of tumor-associated cytokines and angiogenesis related factors, and provide clinical evidence for studying the mechanisms on the metastasis in GC, OS and ES.

Keywords:  Ewing’s sarcoma; Giant cell tumor of bone; metastasis; osteosarcoma

DOI:  https://doi.org/10.3233/THC-218010
Front Oncol. 2020 ;10 622956

Autophagy-Mediated Exosomes as Immunomodulators of Natural Killer Cells in Pancreatic Cancer Microenvironment.

Daniela L Papademetrio, María Noé Garcia, Daniel Grasso, Élida Alvarez.

  Pancreas ductal adenocarcinoma is a highly aggressive cancer with an incredible poor lifespan. Different chemotherapeutic agents' schemes have been tested along the years without significant success. Furthermore, immunotherapy also fails to cope with the disease, even in combination with other standard approaches. Autophagy stands out as a chemoresistance mechanism and is also becoming relevant as responsible for the inefficacy of immunotherapy. In this complex scenario, exosomes have emerged as a new key player in tumor environment. Exosomes act as messengers among tumor cells, including tumor microenvironment immune cells. For instance, tumor-derived exosomes are capable of generating a tolerogenic microenvironment, which in turns conditions the immune system behavior. But also, immune cells-derived exosomes, under non-tolerogenic conditions, induce tumor suppression, although they are able to promote chemoresistance. In that way, NK cells are well known key regulators of carcinogenesis and the inhibition of their function is detrimental for tumor suppression. Additionally, increasing evidence suggests a crosstalk between exosome biogenesis and the autophagy pathway. This mini review has the intention to summarize the available data in the complex relationships between the autophagy pathway and the broad spectrum of exosomes subpopulations in pancreatic cancer, with focus on the NK cells response.

Keywords:  autophagy; exosomes; natural killer cells; pancreatic cancer; tumor microenvironment

DOI:  https://doi.org/10.3389/fonc.2020.622956
Cancer Treat Res Commun. 2021 Jan 21. pii: S2468-2942(21)00016-2. [Epub ahead of print]27 100317

High gene expression of estrogen and progesterone receptors is associated with decreased t cell infiltration in patients with NSCLC.

Michael S Oh, Jonathan F Anker, Young Kwang Chae.

   OBJECTIVES: Prior studies have demonstrated that signaling via the estrogen and progesterone receptors (ER and PR) may affect prognosis in non-small cell lung cancer (NSCLC). The precise impact of hormone signaling on clinical outcomes in NSCLC, especially in the context of immune checkpoint blockade, remains unclear.
MATERIALS AND METHODS: We obtained RNA-Seq data from The Cancer Genome Atlas (TCGA) to determine mRNA expression levels of ESR1 (ER-α), ESR2 (ER-β), PGR (PR), CYP19A1 (aromatase), and immune-related genes. Tumor infiltration by activated T cells was predicted based on expression of immune metagenes.
RESULTS: High levels of both ESR1 and PGR were associated with significantly decreased tumor infiltration by CD4+ and CD8+ activated T cells. CYP19A1 expression was associated with decreased CD4+ but not CD8+ T cell infiltration. There were no significant differences based on ESR2. These findings persisted after stratifying patients based on sex and tumor histology. In addition, increased ESR1 was associated with high gene expression of immune checkpoint markers, while increased PGR was associated with high levels of TGF-β genes. In a multivariate logistic regression analysis, ESR1, PGR, TGFB1, and the total number of somatic variants were identified as independent factors predicting T cell infiltration.
CONCLUSIONS: Increased gene expression of ER-α and PR was associated with decreased activated T cell infiltration in patients with NSCLC. The relevance of hormone receptor status should be validated clinically, including in the context of immune checkpoint inhibitors.

Keywords:  Estrogen receptor; Immune checkpoint; Lung cancer; Progesterone receptor; Tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.1016/j.ctarc.2021.100317