Hypoxia-Dependent Inhibition of Tumor Cell Susceptibility to CTL-Mediated Lysis Involves NANOG Induction in Target Cells.
Summary of "Hypoxia-Dependent Inhibition of Tumor Cell Susceptibility to CTL-Mediated Lysis Involves NANOG Induction in Target Cells."
Hypoxia is a major feature of the solid tumor microenvironment and is known to be associated with tumor progression and poor clinical outcome. Recently, we reported that hypoxia protects human non-small cell lung tumor cells from specific lysis by stabilizing hypoxia-inducible factor-1α and inducing STAT3 phosphorylation. In this study, we show that NANOG, a transcription factor associated with stem cell self renewal, is a new mediator of hypoxia-induced resistance to specific lysis. Our data indicate that under hypoxic conditions, NANOG is induced at both transcriptional and translational levels. Knockdown of the NANOG gene in hypoxic tumor cells is able to significantly attenuate hypoxia-induced tumor resistance to CTL-dependent killing. Such knockdown correlates with an increase of target cell death and an inhibition of hypoxia-induced delay of DNA replication in these cells. Interestingly, NANOG depletion results in inhibition of STAT3 phosphorylation and nuclear translocation. To our knowledge, this study is the first to show that hypoxia-induced NANOG plays a critical role in tumor cell response to hypoxia and promotes tumor cell resistance to Ag-specific lysis.
Affiliation
Institut Gustave Roussy, INSERM Unité 753, 94800 Villejuif, France;
Journal Details
This article was published in the following journal.
Name: Journal of immunology (Baltimore, Md. : 1950)
ISSN: 1550-6606
Pages: 4031-9
Links
- PubMed Source: http://www.ncbi.nlm.nih.gov/pubmed/21911602
- DOI: http://dx.doi.org/10.4049/jimmunol.1101011
Medical and Biotech [MESH] Definitions
Cell Migration Inhibition
Phenomenon of cell-mediated immunity measured by in vitro inhibition of the migration or phagocytosis of antigen-stimulated LEUKOCYTES or MACROPHAGES. Specific CELL MIGRATION ASSAYS have been developed to estimate levels of migration inhibitory factors, immune reactivity against tumor-associated antigens, and immunosuppressive effects of infectious microorganisms.
Beta-aminoethyl Isothiourea
A radiation-protective agent that can inhibit DNA damage by binding to the DNA. It also increases the susceptibility of blood cells to complement-mediated lysis.
Signal Transduction
The intracellular transfer of information (biological activation/inhibition) through a signal pathway. In each signal transduction system, an activation/inhibition signal from a biologically active molecule (hormone, neurotransmitter) is mediated via the coupling of a receptor/enzyme to a second messenger system or to an ion channel. Signal transduction plays an important role in activating cellular functions, cell differentiation, and cell proliferation. Examples of signal transduction systems are the GAMMA-AMINOBUTYRIC ACID-postsynaptic receptor-calcium ion channel system, the receptor-mediated T-cell activation pathway, and the receptor-mediated activation of phospholipases. Those coupled to membrane depolarization or intracellular release of calcium include the receptor-mediated activation of cytotoxic functions in granulocytes and the synaptic potentiation of protein kinase activation. Some signal transduction pathways may be part of larger signal transduction pathways; for example, protein kinase activa
Leukocyte Adherence Inhibition Test
Test for cell-mediated antitumor immunity and related serum blocking factors based on the finding that leukocytes from cancer patients, but not from controls, when mixed in vitro with antigenic extracts of tumors of the same histological type, undergo a diminution in their normal adherence to glass surfaces. Sera from tumor-bearing patients block the LAI reaction of their own leukocytes or those of other patients with the same type of tumor.
Cyclin-dependent Kinase Inhibitor P21
A cyclin-dependent kinase inhibitor that mediates TUMOR SUPPRESSOR PROTEIN P53-dependent CELL CYCLE arrest. p21 interacts with a range of CYCLIN-DEPENDENT KINASES and associates with PROLIFERATING CELL NUCLEAR ANTIGEN and CASPASE 3.
PubMed Articles
Tyrosine kinase pathways modulate tumor susceptibility to natural killer cells.
Natural killer (NK) cells are primary effectors of innate immunity directed against transformed tumor cells. In response, tumor cells have developed mechanisms to evade NK cell-mediated lysis through...
The tumor suppressor gene von Hippel-Lindau (VHL) is involved in the development of sporadic clear-cell renal cell carcinoma (RCC). VHL interferes with angiogenesis and also controls cell adhesion and...
Hypoxia is a common environmental stress. Particularly, the center of rapidly-growing solid tumors is easily exposed to hypoxic conditions. Hypoxia is well-known to attenuate the therapeutic response...
Upon exposure to nitrogen-containing bisphosphonates (N-BPs) such as zoledronic acid (Zol), human tumor cells increase susceptibility to γδ T cell-mediated cytotoxicity. Based on this finding, much...
Actin-sequestering protein, thymosin beta-4, is a novel hypoxia responsive regulator.
Angiogenesis is induced by soluble factors such as vascular endothelial growth factor (VEGF) released from tumor cells in hypoxia. It enhances solid tumor growth and provides an ability to establish m...
Clinical Trials
Fasturtec TLS Treatment / Prophylysis
An open-label study to determine the efficacy and safety of Rasburicase used for the prevention and treatment of tumor lysis syndrome
Pilot Study of (61)CuATSM-PET Imaging in Cancer Patients
Hypoxia is a key factor in malignant progression of a neoplasm. It is our aim to explore the basis for quantitative in vivo tumor imaging by Cu-61 diacetyl-bis(N4-methylthiosemicarbazone)P...
Identification of Serum Markers For Tumor Hypoxia in Non-Small Cell Lung Cancers
The purpose of the study is to identify a surrogate serum marker for tumor hypoxia in patients with lung cancers.
Liver resection and liver transplantation are the acceptable treatment of Hepatocellular Carcinoma (HCC). But the long-term survival is unsatisfactory as a result of high rate of intra and...
Rasburicase in Patients at Risk for Tumor Lysis Syndrome
Primary Objectives: To determine the efficacy of rasburicase administered as a single dose followed by as needed dosing (investigational arm) as compared to fixed dosing for 5 days (stand...
