scholarly journals Metabolic remodeling of the tumor microenvironment: Migration stimulating factor (MSF) reprograms myofibroblasts toward lactate production, fueling anabolic tumor growth

Cell Cycle ◽  
2012 ◽  
Vol 11 (18) ◽  
pp. 3403-3414 ◽  
Author(s):  
Valentina Carito ◽  
Gloria Bonuccelli ◽  
Ubaldo E. Martinez-Outschoorn ◽  
Diana Whitaker-Menezes ◽  
Maria Cristina Caroleo ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Growth ◽  
Lactate Production ◽  
Metabolic Remodeling ◽  
Migration Stimulating Factor ◽  
Stimulating Factor

scholarly journals The Key Role of the WNT/β-Catenin Pathway in Metabolic Reprogramming in Cancers under Normoxic Conditions

Cancers ◽  
2021 ◽  
Vol 13 (21) ◽  
pp. 5557
Author(s):  
Alexandre Vallée ◽  
Yves Lecarpentier ◽  
Jean-Noël Vallée
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Growth ◽  
Warburg Effect ◽  
Target Genes ◽  
Glucose Transporter ◽  
Aerobic Glycolysis ◽  
Lactate Production ◽  
Metabolic Reprogramming ◽  
Pyruvate Dehydrogenase Kinase ◽  
The Warburg Effect

The canonical WNT/β-catenin pathway is upregulated in cancers and plays a major role in proliferation, invasion, apoptosis and angiogenesis. Nuclear β-catenin accumulation is associated with cancer. Hypoxic mechanisms lead to the activation of the hypoxia-inducible factor (HIF)-1α, promoting glycolytic and energetic metabolism and angiogenesis. However, HIF-1α is degraded by the HIF prolyl hydroxylase under normoxia, conditions under which the WNT/β-catenin pathway can activate HIF-1α. This review is therefore focused on the interaction between the upregulated WNT/β-catenin pathway and the metabolic processes underlying cancer mechanisms under normoxic conditions. The WNT pathway stimulates the PI3K/Akt pathway, the STAT3 pathway and the transduction of WNT/β-catenin target genes (such as c-Myc) to activate HIF-1α activity in a hypoxia-independent manner. In cancers, stimulation of the WNT/β-catenin pathway induces many glycolytic enzymes, which in turn induce metabolic reprogramming, known as the Warburg effect or aerobic glycolysis, leading to lactate overproduction. The activation of the Wnt/β-catenin pathway induces gene transactivation via WNT target genes, c-Myc and cyclin D1, or via HIF-1α. This in turn encodes aerobic glycolysis enzymes, including glucose transporter, hexokinase 2, pyruvate kinase M2, pyruvate dehydrogenase kinase 1 and lactate dehydrogenase-A, leading to lactate production. The increase in lactate production is associated with modifications to the tumor microenvironment and tumor growth under normoxic conditions. Moreover, increased lactate production is associated with overexpression of VEGF, a key inducer of angiogenesis. Thus, under normoxic conditions, overstimulation of the WNT/β-catenin pathway leads to modifications of the tumor microenvironment and activation of the Warburg effect, autophagy and glutaminolysis, which in turn participate in tumor growth.

scholarly journals 695 Oral delivery of a microbial extracellular vesicle induces potent anti-tumor immunity in mice

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A737-A737
Author(s):  
Loise Francisco-Anderson ◽  
Loise Francisco-Anderson ◽  
Mary Abdou ◽  
Michael Goldberg ◽  
Erin Troy ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Growth ◽  
Extracellular Vesicles ◽  
Tumor Immunity ◽  
Extracellular Vesicle ◽  
The Body ◽  
Checkpoint Inhibition ◽  
Small Intestinal ◽  
The Impact

BackgroundThe small intestinal axis (SINTAX) is a network of anatomic and functional connections between the small intestine and the rest of the body. It acts as an immunosurveillance system, integrating signals from the environment that affect physiological processes throughout the body. The impact of events in the gut in the control of tumor immunity is beginning to be appreciated. We have previously shown that an orally delivered single strain of commensal bacteria induces anti-tumor immunity preclinically via pattern recognition receptor-mediated activation of innate and adaptive immunity. Some bacteria produce extracellular vesicles (EVs) that share molecular content with the parent bacterium in a particle that is roughly 1/1000th the volume in a non-replicating form. We report here an orally-delivered and gut-restricted bacterial EV which potently attenuates tumor growth to a greater extent than whole bacteria or checkpoint inhibition.MethodsEDP1908 is a preparation of extracellular vesicles produced by a gram-stain negative strain of bacterium of the Oscillospiraceae family isolated from a human donor. EDP1908 was selected for its immunostimulatory profile in a screen of EVs from a range of distinct microbial strains. Its mechanism of action was determined by ex vivo analysis of the tumor microenvironment (TME) and by in vitro functional studies with murine and human cells.ResultsOral treatment of tumor-bearing mice with EDP1908 shows superior control of tumor growth compared to checkpoint inhibition (anti-PD-1) or an intact microbe. EDP1908 significantly increased the percentage of IFNγ and TNF producing CD8+ CTLs, NK cells, NKT cells and CD4+ cells in the tumor microenvironment (TME). EDP1908 also increased tumor-infiltrating dendritic cells (DC1 and DC2). Analysis of cytokines in the TME showed significant increases in IP-10 and IFNg production in mice treated with EDP1908, creating an environment conducive to the recruitment and activation of anti-tumor lymphocytes.ConclusionsThis is the first report of striking anti-tumor effects of an orally delivered microbial extracellular vesicle. These data point to oral EVs as a new class of immunotherapeutic drugs. They are particularly effective at harnessing the biology of the small intestinal axis, acting locally on host cells in the gut to control distal immune responses within the TME. EDP1908 is in preclinical development for the treatment of cancer.Ethics ApprovalPreclinical murine studies were conducted under the approval of the Avastus Preclinical Services’ Ethics Board. Human in vitro samples were attained by approval of the IntegReview Ethics Board; informed consent was obtained from all subjects.

scholarly journals A TLR4 agonist improves immune checkpoint blockade treatment by increasing the ratio of effector to regulatory cells within the tumor microenvironment

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
A. Farias ◽  
A. Soto ◽  
F. Puttur ◽  
C. J. Goldin ◽  
S. Sosa ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Growth ◽  
Therapeutic Effect ◽  
Immune Cells ◽  
Immune Checkpoint ◽  
Combined Treatment ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Regulatory Cells ◽  
Ifn Γ

AbstractBrucella lumazine synthase (BLS) is a homodecameric protein that activates dendritic cells via toll like receptor 4, inducing the secretion of pro-inflammatory cytokines and chemokines. We have previously shown that BLS has a therapeutic effect in B16 melanoma-bearing mice only when administered at early stages of tumor growth. In this work, we study the mechanisms underlying the therapeutic effect of BLS, by analyzing the tumor microenvironment. Administration of BLS at early stages of tumor growth induces high levels of serum IFN-γ, as well as an increment of hematopoietic immune cells within the tumor. Moreover, BLS-treatment increases the ratio of effector to regulatory cells. However, all treated mice eventually succumb to the tumors. Therefore, we combined BLS administration with anti-PD-1 treatment. Combined treatment increases the outcome of both monotherapies. In conclusion, we show that the absence of the therapeutic effect at late stages of tumor growth correlates with low levels of serum IFN-γ and lower infiltration of immune cells in the tumor, both of which are essential to delay tumor growth. Furthermore, the combined treatment of BLS and PD-1 blockade shows that BLS could be exploited as an essential immunomodulator in combination therapy with an immune checkpoint blockade to treat skin cancer.

scholarly journals Intratumoral Canine Distemper Virus Infection Inhibits Tumor Growth by Modulation of the Tumor Microenvironment in a Murine Xenograft Model of Canine Histiocytic Sarcoma

2021 ◽  
Vol 22 (7) ◽  
pp. 3578
Author(s):  
Federico Armando ◽  
Adnan Fayyad ◽  
Stefanie Arms ◽  
Yvonne Barthel ◽  
Dirk Schaudien ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Virus Infection ◽  
Tumor Growth ◽  
Canine Distemper Virus ◽  
Xenograft Model ◽  
Histiocytic Sarcoma ◽  
Oncolytic Viruses ◽  
Canine Distemper ◽  
Murine Xenograft Model ◽  
The Impact

Histiocytic sarcomas refer to highly aggressive tumors with a poor prognosis that respond poorly to conventional treatment approaches. Oncolytic viruses, which have gained significant traction as a cancer therapy in recent decades, represent a promising option for treating histiocytic sarcomas through their replication and/or by modulating the tumor microenvironment. The live attenuated canine distemper virus (CDV) vaccine strain Onderstepoort represents an attractive candidate for oncolytic viral therapy. In the present study, oncolytic virotherapy with CDV was used to investigate the impact of this virus infection on tumor cell growth through direct oncolytic effects or by virus-mediated modulation of the tumor microenvironment with special emphasis on angiogenesis, expression of selected MMPs and TIMP-1 and tumor-associated macrophages in a murine xenograft model of canine histiocytic sarcoma. Treatment of mice with xenotransplanted canine histiocytic sarcomas using CDV induced overt retardation in tumor progression accompanied by necrosis of neoplastic cells, increased numbers of intratumoral macrophages, reduced angiogenesis and modulation of the expression of MMPs and TIMP-1. The present data suggest that CDV inhibits tumor growth in a multifactorial way, including direct cell lysis and reduction of angiogenesis and modulation of MMPs and their inhibitor TIMP-1, providing further support for the concept of its role in oncolytic therapies.

scholarly journals TMIC-24. COLONY STIMULATING FACTOR 1 INHIBITION DECREASES TUMOR GROWTH AND MACROPHAGE INFILTRATION, AND INCREASES NEUTROPHIL INFILTRATION IN XENOGRAFT MICE MODELS OF GLIOBLASTOMA

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi252-vi252
Author(s):  
Sabbir Khan ◽  
Yuji Piao ◽  
Sandeep Mittal ◽  
Kain McGee ◽  
Soon Park ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Mouse Models ◽  
Myeloid Cell ◽  
Neutrophil Infiltration ◽  
Macrophage Infiltration ◽  
Colony Stimulating Factor ◽  
Vegf Inhibitors ◽  
Mesenchymal Transition ◽  
Vegf Inhibition ◽  
Stimulating Factor

Abstract Glioblastoma (GBM) is the most common, highly aggressive and lethal primary brain tumor in adults, and has a median overall survival ranging from 12 to 15 months. Several human cancers including glioma are infiltrated with numerous immune cell types which play a critical role in tumor growth, invasion and resistance to treatment. Previous studies, including our group, have shown that resistance to anti-VEGF therapy is associated with myeloid cell infiltration and mesenchymal transition in GBM. Notably, most glioma patients have shown increase in CD68+ cells due to overproduction of colony stimulating factor 1 (CSF-1) by tumor cells, a growth factor for macrophages. Therefore, we hypothesized that CSF-1 inhibition may reduce macrophage and/or myeloid cell infiltration in glioma, thereby increasing animal survival as monotherapy or in combination with VEGF inhibitors in xenograft GBM mouse models. We tested two CSF-1R inhibitors (AZD 7507 and JNJ-28312141) alone and in combination with VEGF inhibition to prevent macrophage infiltration in xenograft GBM mouse models. CSF-1R and VEGF inhibitors reduced macrophage infiltration (F4/80 staining), tumor volume, and mesenchymal transition (YKL-40 staining), and there was a marginal survival benefit in this model. Interestingly, despite significant reduction in tumor macrophages, we observed a significant increase in neutrophil infiltration and hypoxia (HIF1α staining), particularly in the combinatorial treated. Considering these observations, we further evaluated tumor-associated neutrophil (TAN) infiltration in GBM patient tumors by fluorescence-activated cell sorting (FACS). FACS-isolated TANs were identified as CD11b+/CD15+/CD66b+ triple positive. Our results shown that the infiltrating TAN population vary from 0.5 to 5% in GBM patient tumors. Detailed characterization of TAN population and polarization in patient tumors are ongoing. Our findings revealed that CSF-1 and VEGF inhibition reduced macrophage infiltration and tumor growth, but significantly increased TAN infiltration which will likely hamper the potential therapeutic benefit of anti-CSF1-directed inhibitors.

Granulocyte-macrophage colony-stimulating factor inhibits tumor growth during the postoperative period

Surgery ◽  
1996 ◽  
Vol 119 (2) ◽  
pp. 178-185 ◽  
Author(s):  
Arnold D.K. Hill ◽  
H. Paul Redmond ◽  
Hassan A. Naama ◽  
David Bouchier-Hayes
Keyword(s):  
Tumor Growth ◽  
Postoperative Period ◽  
Colony Stimulating Factor ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

Hsa_circ_0023990 Promotes Tumor Growth and Glycolysis in Dedifferentiated TC via Targeting miR-485-5p/FOXM1 Axis

Endocrinology ◽  
2021 ◽  
Vol 162 (12) ◽  
Author(s):  
Qing Zhang ◽  
Lian Wu ◽  
Shao-Zheng Liu ◽  
Qing-Jie Chen ◽  
Ling-Peng Zeng ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Tumor Growth ◽  
Radioactive Iodine ◽  
Lactate Production ◽  
Luciferase Reporter ◽  
Current Therapy ◽  
Biological Processes ◽  
Reporter Assay ◽  
Potential Therapeutic Target

Abstract Background During the transformation to dedifferentiated thyroid cancer (TC) types, the ability of papillary thyroid carcinomas (PTCs) to concentrate radioactive iodine might be lost, raising difficulty for the current therapy. circRNAs were proved to be implicated in the progression of various cancers. In this study, we aimed to investigate the functional role and mechanism of hsa_circ_0023990 in dedifferentiated TC. Methods The expression pattern of genes were detected using quantitative PCR or western blot assays. Cell proliferation was determined by CCK8, colony formation, EdU, and cell-cycle assays. Glycolysis was assessed using glucose uptake and lactate production assays. Luciferase reporter assay was performed to examine the interactions between miR-485-5p and hsa_circ_0023990 or FOXM1. Xenograft assay was allowed for observation of tumor growth in vivo. Results Hsa_circ_0023990 and FOXM1 were upregulated in dedifferentiated TC tissues and cell lines. The higher level of hsa_circ_0023900 could stimulate the proliferation and glycolysis of dedifferentiated TC cells via positively regulating FOXM1. Mechanistically, miR-485-5p was demonstrated to interact with hsa_circ_0023990 and FOXM1 and involved in the regulation of has_circ_0023990 and FOXM1 in TC biological processes. Conclusion Our results discovered the functional network of hsa_circ_0023990 in dedifferentiated TC development by facilitating cell proliferation and glycolysis via miR-485-5p/FOXM1 axis, implying that hsa_circ_0023990 might be a potential therapeutic target for the dedifferentiated TC treatment.

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