Wnt Signaling in the Tumor Microenvironment.
TL;DR: The Wnt pathway, the role of Wnt signaling in different components of the TME, and therapeutic strategies for targeting Wnt signaled cells are reviewed.
Abstract: Dysregulated Wnt signaling plays a central role in initiation, progression, and metastasis in many types of human cancers. Cancer development and resistance to conventional cancer therapies are highly associated with the tumor microenvironment (TME), which is composed of numerous stable non-cancer cells, including immune cells, extracellular matrix (ECM), fibroblasts, endothelial cells (ECs), and stromal cells. Recently, increasing evidence suggests that the relationship between Wnt signaling and the TME promotes the proliferation and maintenance of tumor cells, including leukemia. Here, we review the Wnt pathway, the role of Wnt signaling in different components of the TME, and therapeutic strategies for targeting Wnt signaling.
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24 Apr 2014
TL;DR: It is reported that selective disruption of the CBP/β- and γ-catenin interactions using ICG-001 leads to differentiation of pre-B ALL cells and loss of self-renewal capacity.
Abstract: Drug resistance in acute lymphoblastic leukemia (ALL) remains a major problem warranting new treatment strategies. Wnt/catenin signaling is critical for the self-renewal of normal hematopoietic progenitor cells. Deregulated Wnt signaling is evident in chronic and acute myeloid leukemia; however, little is known about ALL. Differential interaction of catenin with either the Kat3 coactivator CREBBP (CREB-binding protein (CBP)) or the highly homologous EP300 (p300) is critical to determine divergent cellular responses and provides a rationale for the regulation of both proliferation and differentiation by the Wnt signaling pathway. Usage of the coactivator CBP by catenin leads to transcriptional activation of cassettes of genes that are involved in maintenance of progenitor cell self-renewal. However, the use of the coactivator p300 leads to activation of genes involved in the initiation of differentiation. ICG-001 is a novel small-molecule modulator of Wnt/catenin signaling, which specifically binds to the N-terminus of CBP and not p300, within amino acids 1–110, thereby disrupting the interaction between CBP and catenin. Here, we report that selective disruption of the CBP/β- and γ-catenin interactions using ICG-001 leads to differentiation of pre-B ALL cells and loss of self-renewal capacity. Survivin, an inhibitor-of-apoptosis protein, was also downregulated in primary ALL after treatment with ICG-001. Using chromatin immunoprecipitation assay, we demonstrate occupancy of the survivin promoter by CBP that is decreased by ICG-001 in primary ALL. CBP mutations have been recently identified in a significant percentage of ALL patients, however, almost all of the identified mutations reported occur C-terminal to the binding site for ICG-001. Importantly, ICG-001, regardless of CBP mutational status and chromosomal aberration, leads to eradication of drug-resistant primary leukemia in combination with conventional therapy in vitro and significantly prolongs the survival of NOD/SCID mice engrafted with primary ALL. Therefore, specifically inhibiting CBP/catenin transcription represents a novel approach to overcome relapse in ALL.
128 citations
TL;DR: The tumor microenvironment plays a pivotal role in tumor initiation and progression by creating a dynamic interaction with cancer cells as mentioned in this paper, as it influences the growth and expansion of malignant cells in various ways.
37 citations
TL;DR: The causes and consequences of fibrous stroma and how this stromal cue is transmitted to the nuclei of parenchymal cells through a physical continuum from the ECM to chromatin, as well as ECM-dependent biochemical signaling that contributes to cellular transformation are summarized.
Abstract: Cumulative evidence shows that fibrogenic stroma and stiff extracellular matrix (ECM) not only result from tumor growth but also play pivotal roles in cellular transformation and tumor initiation. This emerging concept may largely account for the increased cancer risk associated with environmental fibrogenic agents, such as asbestos and silica, and with chronic conditions that are fibrogenic, such as obesity and diabetes. It may also contribute to poor outcomes in patients treated with certain chemotherapeutics that can promote fibrosis, such as bleomycin and methotrexate. Although the mechanistic details of this phenomenon are still being unraveled, we provide an overview of the experimental evidence linking fibrogenic stroma and tumor initiation. In this Review, we will summarize the causes and consequences of fibrous stroma and how this stromal cue is transmitted to the nuclei of parenchymal cells through a physical continuum from the ECM to chromatin, as well as ECM-dependent biochemical signaling that contributes to cellular transformation. Description Myofibroblasts and stiff extracellular matrix are both causes and effects of tumorigenesis.
11 citations
TL;DR: In this paper, a review of the most relevant studies that have shown the effects of nanotherapeutics in cancer treatment is presented. And although the studies analyzed are mostly preclinical, they believe that there is strong evidence that nanoparticles can increase the chances of a better prognosis to cancer in the future.
8 citations
TL;DR: Wang et al. as discussed by the authors investigated the function of MIR155HG in glioma at the transcriptome level and relationship with immune infiltration, and they found that the expression was regulated by DNA promoter methylation and transcription factor (SP1) binding to the promoter.
Abstract: The lncRNA MIR155 host gene (MIR155HG) plays a role in the progression of several malignant cancers. However, the specific mechanisms of MIR155HG in glioma progression have not been clearly established. The purpose of this study was to investigate the function of MIR155HG in glioma at the transcriptome level and relationship with immune infiltration.Totally, 697 RNA-seq and 594 DNA methylation data were retrieved from The Cancer Genome Atlas (TCGA) dataset while 325 RNA-seq data were retrieved from the Chinese Glioma Genome Atlas (CGGA) dataset. The DNA methylation levels of MIR155HG CpG islands were assessed through bisulfite amplicon sequencing (BSAS). The regulatory mechanism of SP1 on MIR155HG was examined by chromatin immunoprecipitation (ChIP) and luciferase reporter assays. R language was used as the main tool for statistical analysis and graphical work.MIR155HG was predominantly expressed in the isocitrate dehydrogenase (IDH) wild-type as well as mesenchymal subtype gliomas. Promoter methylation levels of MIR155HG in glioblastoma (GBM) were remarkably decreased compared with those in lower-grade glioma (LGG). In addition, there were negative correlations between promoter methylation levels and MIR155HG expressions but positive correlations with patients' overall survival. In vitro studies further revealed that MIR155HG expression was regulated by DNA promoter methylation and transcription factor (SP1) binding to the promoter. Moreover, there was a close association between MIR155HG expression and immune as well as stromal cell infiltrations, inflammatory activities, and immune checkpoints. Clinically, univariate and multivariate Cox analyses revealed that MIR155HG is an independent prognostic marker for glioma patients.Our results established that MIR155HG is a potential biomarker for prognosis and an immunotherapeutic target in glioma.
5 citations
References
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TL;DR: A unifying conceptual framework called “cancer immunoediting,” which integrates the immune system’s dual host-protective and tumor-promoting roles is discussed.
Abstract: Understanding how the immune system affects cancer development and progression has been one of the most challenging questions in immunology. Research over the past two decades has helped explain why the answer to this question has evaded us for so long. We now appreciate that the immune system plays a dual role in cancer: It can not only suppress tumor growth by destroying cancer cells or inhibiting their outgrowth but also promote tumor progression either by selecting for tumor cells that are more fit to survive in an immunocompetent host or by establishing conditions within the tumor microenvironment that facilitate tumor outgrowth. Here, we discuss a unifying conceptual framework called "cancer immunoediting," which integrates the immune system's dual host-protective and tumor-promoting roles.
5,026 citations
TL;DR: New-generation combinatorial therapies may overcome resistance mechanisms to immune checkpoint therapy, and evidence points to alterations that converge on the antigen presentation and interferon-γ signaling pathways.
Abstract: The release of negative regulators of immune activation (immune checkpoints) that limit antitumor responses has resulted in unprecedented rates of long-lasting tumor responses in patients with a variety of cancers. This can be achieved by antibodies blocking the cytotoxic T lymphocyte–associated protein 4 (CTLA-4) or the programmed cell death 1 (PD-1) pathway, either alone or in combination. The main premise for inducing an immune response is the preexistence of antitumor T cells that were limited by specific immune checkpoints. Most patients who have tumor responses maintain long-lasting disease control, yet one-third of patients relapse. Mechanisms of acquired resistance are currently poorly understood, but evidence points to alterations that converge on the antigen presentation and interferon-γ signaling pathways. New-generation combinatorial therapies may overcome resistance mechanisms to immune checkpoint therapy.
3,736 citations
TL;DR: Insights gained from understanding how the Wnt pathway is integrally involved in both stem cell and cancer cell maintenance and growth in the intestinal, epidermal and haematopoietic systems may serve as a paradigm for understanding the dual nature of self-renewal signals.
Abstract: The canonical Wnt cascade has emerged as a critical regulator of stem cells. In many tissues, activation of Wnt signalling has also been associated with cancer. This has raised the possibility that the tightly regulated self-renewal mediated by Wnt signalling in stem and progenitor cells is subverted in cancer cells to allow malignant proliferation. Insights gained from understanding how the Wnt pathway is integrally involved in both stem cell and cancer cell maintenance and growth in the intestinal, epidermal and haematopoietic systems may serve as a paradigm for understanding the dual nature of self-renewal signals.
3,625 citations
Institute for Systems Biology1, BC Cancer Agency2, University of California, San Francisco3, University of North Carolina at Chapel Hill4, Columbia University5, Discovery Institute6, Massachusetts Institute of Technology7, Arizona State University8, Sage Bionetworks9, Harvard University10, Johns Hopkins University11, Stanford University12, University of Calgary13, Université libre de Bruxelles14, University of Texas MD Anderson Cancer Center15, Medical College of Wisconsin16, Qatar Airways17, Cold Spring Harbor Laboratory18, University of São Paulo19, Henry Ford Hospital20, University of Alabama at Birmingham21, Van Andel Institute22, Stony Brook University23
TL;DR: An extensive immunogenomic analysis of more than 10,000 tumors comprising 33 diverse cancer types by utilizing data compiled by TCGA identifies six immune subtypes that encompass multiple cancer types and are hypothesized to define immune response patterns impacting prognosis.
3,246 citations
TL;DR: The core Wnt/β-catenin signaling pathway is described, how it controls stem cells, and contributes to disease, and strategies for Wnt-based therapies are discussed.
2,663 citations