Search results for "loi"

Imiquimod inhibits growth and induces differentiation of myeloid leukemia cell lines

2018

Background: The antitumoral effects of different Toll-like receptor (TLRs) agonists is mediated by activating immune responses to suppress tumors growth, although TLR ligands may also have a direct effect on tumoral cells. Given that TLR signaling induces hematopoietic cell differentiations this may serve as a novel differentiation therapeutic approach for AML. Methods: We investigated the effects of agonists for the ten human TLRs on the proliferation, apoptosis, cell cycle and differentiation of ten different types of myeloid leukemia cell lines (HL-60, U-937, KG-1, KG-1a, K-562, Kasumi-1, EOL-1, NB4, MOLM-13 and HEL). Proliferation was measured using the CellTiter 96 (R) Aqueous One Solu…

Transcriptional Profiles and Stromal Changes Reveal Bone Marrow Adaptation to Early Breast Cancer in Association with Deregulated Circulating microRN…

2020

Abstract The presence of a growing tumor establishes a chronic state of inflammation that acts locally and systemically. Bone marrow responds to stress signals by expanding myeloid cells endowed with immunosuppressive functions, further fostering tumor growth and dissemination. How early in transformation the cross-talk with the bone marrow begins and becomes detectable in blood is unknown. Here, gene expression profiling of the bone marrow along disease progression in a spontaneous model of mammary carcinogenesis demonstrates that transcriptional modifications in the hematopoietic compartment occurred as early as preinvasive disease stages. The transcriptional profile showed downregulation…

Nicotinamide Phosphoribosyltransferase Acts as a Metabolic Gate for Mobilization of Myeloid-Derived Suppressor Cells

2019

Abstract Cancer induces alteration of hematopoiesis to fuel disease progression. We report that in tumor-bearing mice the macrophage colony-stimulating factor elevates the myeloid cell levels of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in the NAD salvage pathway, which acts as negative regulator of the CXCR4 retention axis of hematopoietic cells in the bone marrow. NAMPT inhibits CXCR4 through a NAD/Sirtuin 1–mediated inactivation of HIF1α-driven CXCR4 gene transcription, leading to mobilization of immature myeloid-derived suppressor cells (MDSC) and enhancing their production of suppressive nitric oxide. Pharmacologic inhibition or myeloid-specific ablation …

Quantitative Imaging of D-2-Hydroxyglutarate in Selected Histological Tissue Areas by a Novel Bioluminescence Technique

2016

Abstract Patients with malignant gliomas have a poor prognosis with average survival of less than one year. Whereas in other tumor entities the characteristics of tumor metabolism are successfully used for therapeutic approaches, such developments are very rare in brain tumors, notably in gliomas. One metabolic feature characteristic of gliomas, in particular diffuse astrocytomas and oligodendroglial tumors, is the variable content of D-2-hydroxyglutarate (D2HG), a metabolite, which was discovered first in this tumor entity. D2HG is generated in large amounts due to various “gain-of–function” mutations in the isocitrate dehydrogenases IDH-1 and IDH-2. Meanwhile, D2HG has been detected in se…

Repurposing of plant alkaloids for cancer therapy: Pharmacology and toxicology.

2019

Drug repurposing (or repositioning) is an emerging concept to use old drugs for new treatment indications. Phytochemicals isolated from medicinal plants have been largely neglected in this context, although their pharmacological activities have been well investigated in the past, and they may have considerable potentials for repositioning. A grand number of plant alkaloids inhibit syngeneic or xenograft tumor growth in vivo. Molecular modes of action in cancer cells include induction of cell cycle arrest, intrinsic and extrinsic apoptosis, autophagy, inhibition of angiogenesis and glycolysis, stress and anti-inflammatory responses, regulation of immune functions, cellular differentiation, a…

2021

Background Malignant melanoma is an immunogenic skin cancer with an increasing global incidence. Advanced stages of melanoma have poor prognoses. Currently, there are no reliable parameters to predict a patient's response to immune checkpoint inhibitor (ICI) therapy. Methods This study highlights the relevance of a distinct immune signature in the blood for response to ICI therapy and overall survival (OS). Therefore, the immune cell composition in the peripheral blood of 45 melanoma patients prior to ICI therapy was analyzed by flow cytometry and complete blood count. Results Responders to ICI therapy displayed an abundance of proliferating CD4+ T cells, an increased lymphocyte-to-monocyte…

Persistent immune stimulation exacerbates genetically driven myeloproliferative disorders via stromal remodeling

2017

Abstract Systemic immune stimulation has been associated with increased risk of myeloid malignancies, but the pathogenic link is unknown. We demonstrate in animal models that experimental systemic immune activation alters the bone marrow stromal microenvironment, disarranging extracellular matrix (ECM) microarchitecture, with downregulation of secreted protein acidic and rich in cysteine (SPARC) and collagen-I and induction of complement activation. These changes were accompanied by a decrease in Treg frequency and by an increase in activated effector T cells. Under these conditions, hematopoietic precursors harboring nucleophosmin-1 (NPM1) mutation generated myeloid cells unfit for normal …

The Functional Crosstalk between Myeloid-Derived Suppressor Cells and Regulatory T Cells within the Immunosuppressive Tumor Microenvironment

2021

Simple Summary Immunotherapy improved the therapeutic landscape for patients with advanced cancer diseases. However, many patients do not benefit from immunotherapy. The bidirectional crosstalk between myeloid-derived suppressor cells (MDSC) and regulatory T cells (Treg) contributes to immune evasion, limiting the success of immunotherapy by checkpoint inhibitors. This review aims to outline the current knowledge of the role and the immunosuppressive properties of MDSC and Treg within the tumor microenvironment (TME). Furthermore, we will discuss the importance of the functional crosstalk between MDSC and Treg for immunosuppression, issuing particularly the role of cell adhesion molecules. …

Innate Sensing through Mesenchymal TLR4/MyD88 Signals Promotes Spontaneous Intestinal Tumorigenesis

2019

Summary MyD88, an adaptor molecule downstream of innate pathways, plays a significant tumor-promoting role in sporadic intestinal carcinogenesis of the Apcmin/+ model, which carries a mutation in the Apc gene. Here, we show that deletion of MyD88 in intestinal mesenchymal cells (IMCs) significantly reduces tumorigenesis in this model. This phenotype is associated with decreased epithelial cell proliferation, altered inflammatory and tumorigenic immune cell infiltration, and modified gene expression similar to complete MyD88 knockout mice. Genetic deletion of TLR4, but not interleukin-1 receptor (IL-1R), in IMCs led to altered molecular profiles and reduction of intestinal tumors similar to …

Mcl-1 targeting could be an intriguing perspective to cure cancer

2018

The Bcl-2 family, which plays important roles in controlling cancer development, is divided into antiapoptotic and proapoptotic members. The change in the balance between these members governs the life and death of the cells. Mcl-1 is an antiapoptotic member of this family and its distribution in normal and cancerous tissues strongly differs from that of Bcl-2. In human cancers, where upregulation of antiapoptotic proteins is common, Mcl-1 expression is regulated independent of Bcl-2 and its inhibition promotes senescence, a major barrier to tumorigenesis. Cancer chemotherapy determines various kinds of responses, such as senescence and autophagy; however, the ideal response to chemotherapy…