Modulation of Angiogenic and Inflammatory Response in Glioblastoma by Hypoxia

Glioblastoma are rapidly proliferating brain tumors in which hypoxia is readily recognizable, as indicated by focal or extensive necrosis and vascular proliferation, two independent diagnostic criteria for glioblastoma. Gene expression profiling of glioblastoma revealed a gene expression signature associated with hypoxia-regulated genes. The correlated gene set emerging from unsupervised analysis comprised known hypoxia-inducible genes involved in angiogenesis and inflammation such as VEGF and BIRC3, respectively. The relationship between hypoxia-modulated angiogenic genes and inflammatory genes was associated with outcome in our cohort of glioblastoma patients treated within prospective clinical trials of combined chemoradiotherapy. The hypoxia regulation of several new genes comprised in this cluster including ZNF395, TNFAIP3, and TREM1 was experimentally confirmed in glioma cell lines and primary monocytes exposed to hypoxia in vitro. Interestingly, the cluster seems to characterize differential response of tumor cells, stromal cells and the macrophage/microglia compartment to hypoxic conditions. Most genes classically associated with the inflammatory compartment are part of the NF-kappaB signaling pathway including TNFAIP3 and BIRC3 that have been shown to be involved in resistance to chemotherapy. Our results associate hypoxia-driven tumor response with inflammation in glioblastoma, hence underlining the importance of tumor-host interaction involving the inflammatory compartment.

[1]  Masahiro Inoue,et al.  Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. , 2009, Cancer cell.

[2]  L. Ramdas,et al.  Altered gene expression in busulfan-resistant human myeloid leukemia. , 2008, Leukemia research.

[3]  Hiroyuki Aburatani,et al.  The S100A8–serum amyloid A3–TLR4 paracrine cascade establishes a pre-metastatic phase , 2008, Nature Cell Biology.

[4]  E. Domany,et al.  Stem cell-related "self-renewal" signature and high epidermal growth factor receptor expression associated with resistance to concomitant chemoradiotherapy in glioblastoma. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[5]  E. Nedivi,et al.  cpg15 and cpg15‐2 constitute a family of activity‐regulated ligands expressed differentially in the nervous system to promote neurite growth and neuronal survival , 2008, The Journal of comparative neurology.

[6]  Hsuan-Yu Chen,et al.  TREM-1 expression in tumor-associated macrophages and clinical outcome in lung cancer. , 2008, American journal of respiratory and critical care medicine.

[7]  S. Vandenberg,et al.  HIF1alpha induces the recruitment of bone marrow-derived vascular modulatory cells to regulate tumor angiogenesis and invasion. , 2008, Cancer cell.

[8]  I. Katsikis,et al.  Kisspeptins: a multifunctional peptide system with a role in reproduction, cancer and the cardiovascular system. , 2008, Hippokratia.

[9]  N. Sato,et al.  Overexpression of papillomavirus binding factor in Ewing's sarcoma family of tumors conferring poor prognosis. , 2008, Oncology reports.

[10]  M. Ornatowska,et al.  TREM‐1 expression in macrophages is regulated at transcriptional level by NF‐κB and PU.1 , 2007, European journal of immunology.

[11]  C. Dumontet,et al.  A20/TNFAIP3, a new estrogen-regulated gene that confers tamoxifen resistance in breast cancer cells , 2007, Oncogene.

[12]  Tao Lu,et al.  Aberrant constitutive activation of nuclear factor κB in glioblastoma multiforme drives invasive phenotype , 2007, Journal of Neuro-Oncology.

[13]  M. Bilban,et al.  Kisspeptins and the placenta: Regulation of trophoblast invasion , 2007, Reviews in Endocrine and Metabolic Disorders.

[14]  A. Davenport,et al.  Kisspeptins are novel potent vasoconstrictors in humans, with a discrete localization of their receptor, G protein-coupled receptor 54, to atherosclerosis-prone vessels. , 2007, Endocrinology.

[15]  De-Pei Liu,et al.  A20 inhibits oxidized low‐density lipoprotein‐induced apoptosis through negative Fas/Fas ligand‐dependent activation of caspase‐8 and mitochondrial pathways in murine RAW264.7 macrophages , 2006, Journal of cellular physiology.

[16]  J. Borén,et al.  Hypoxia Converts Human Macrophages Into Triglyceride-Loaded Foam Cells , 2006, Arteriosclerosis, thrombosis, and vascular biology.

[17]  David J. Yang,et al.  The role of human glioma-infiltrating microglia/macrophages in mediating antitumor immune responses. , 2006, Neuro-oncology.

[18]  Nolwenn Le Meur,et al.  Characterization of the expression of the hypoxia‐induced genes neuritin, TXNIP and IGFBP3 in cancer , 2006, FEBS letters.

[19]  Jayant P. Menon,et al.  Neuronal and glioma-derived stem cell factor induces angiogenesis within the brain. , 2006, Cancer cell.

[20]  Thomas D. Wu,et al.  Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis. , 2006, Cancer cell.

[21]  J. Pollard,et al.  Distinct role of macrophages in different tumor microenvironments. , 2006, Cancer research.

[22]  L. Recht,et al.  Tumor Necrosis Factor-α–Induced Protein 3 As a Putative Regulator of Nuclear Factor-κB–Mediated Resistance to O6-Alkylating Agents in Human Glioblastomas , 2006 .

[23]  L. Recht,et al.  Tumor necrosis factor-alpha-induced protein 3 as a putative regulator of nuclear factor-kappaB-mediated resistance to O6-alkylating agents in human glioblastomas. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[24]  Mutsushi Yamasaki,et al.  Expression of the inhibitors of apoptosis proteins in cisplatin-resistant prostate cancer cells. , 2005, Oncology reports.

[25]  K. Murphy.  Kisspeptins: Regulators of Metastasis and the Hypothalamic‐Pituitary‐Gonadal Axis , 2005, Journal of neuroendocrinology.

[26]  Martin J. van den Bent,et al.  Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. , 2005, The New England journal of medicine.

[27]  R. Mirimanoff,et al.  MGMT gene silencing and benefit from temozolomide in glioblastoma. , 2005, The New England journal of medicine.

[28]  A. Harris,et al.  Pyruvate dehydrogenase and pyruvate dehydrogenase kinase expression in non small cell lung cancer and tumor-associated stroma. , 2005, Neoplasia.

[29]  S. Horvath,et al.  Gene Expression Profiling of Gliomas Strongly Predicts Survival , 2004, Cancer Research.

[30]  J. Ikeda,et al.  Novel Nuclear Shuttle Proteins, HDBP1 and HDBP2, Bind to Neuronal Cell-specific cis-Regulatory Element in the Promoter for the Human Huntington's Disease Gene* , 2004, Journal of Biological Chemistry.

[31]  W. Garvey,et al.  Facilitative glucose transporter gene expression in human lymphocytes, monocytes, and macrophages: a role for GLUT isoforms 1, 3, and 5 in the immune response and foam cell formation. , 2004, Blood cells, molecules & diseases.

[32]  Eytan Domany,et al.  Classification of human astrocytic gliomas on the basis of gene expression: a correlated group of genes with angiogenic activity emerges as a strong predictor of subtypes. , 2003, Cancer research.

[33]  M. Tabata,et al.  c-IAP1 is overexpressed in HL-60 cells selected for doxorubicin resistance: effects on etoposide-induced apoptosis. , 2003, Anticancer research.

[34]  L. Nabors,et al.  Tumor necrosis factor alpha induces angiogenic factor up-regulation in malignant glioma cells: a role for RNA stabilization and HuR. , 2003, Cancer research.

[35]  J. Pfeilschifter,et al.  Regulation of inhibitor of apoptosis expression by nitric oxide and cytokines: relation to apoptosis induction in rat mesangial cells and raw 264.7 macrophages. , 2001, Journal of the American Society of Nephrology : JASN.

[36]  M. Colonna,et al.  TREM-1 amplifies inflammation and is a crucial mediator of septic shock , 2001, Nature.

[37]  Chulhee Choi,et al.  CXC Chemokine Receptor 4 Expression and Function in Human Astroglioma Cells1 , 2001, The Journal of Immunology.

[38]  R. Beyaert,et al.  A20 and A20-binding proteins as cellular inhibitors of nuclear factor-kappa B-dependent gene expression and apoptosis. , 2000, Biochemical pharmacology.

[39]  M. Colonna,et al.  Cutting Edge: Inflammatory Responses Can Be Triggered by TREM-1, a Novel Receptor Expressed on Neutrophils and Monocytes1 , 2000, The Journal of Immunology.

[40]  G. Getz,et al.  Coupled two-way clustering analysis of gene microarray data. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[41]  E. Tremoli,et al.  Increased Thrombogenic Potential of Human Monocyte-derived Macrophages Spontaneously Transformed into Foam Cells , 1999, Thrombosis and Haemostasis.

[42]  G. Semenza,et al.  Regulation of mammalian O2 homeostasis by hypoxia-inducible factor 1. , 1999, Annual review of cell and developmental biology.

[43]  Erwin G. Van Meir,et al.  Upregulation of Interleukin 8 by Oxygen-deprived Cells in Glioblastoma Suggests a Role in Leukocyte Activation, Chemotaxis, and Angiogenesis , 1997, The Journal of experimental medicine.

[44]  M. Malim,et al.  Suppression of tumor necrosis factor-induced cell death by inhibitor of apoptosis c-IAP2 is under NF-kappaB control. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[45]  A. Tall,et al.  Interleukin 8 Is Induced by Cholesterol Loading of Macrophages and Expressed by Macrophage Foam Cells in Human Atheroma (*) , 1996, The Journal of Biological Chemistry.

[46]  E. Keshet,et al.  Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis , 1992, Nature.

[47]  Georg Breier,et al.  Vascular endothelial growth factor is a potential tumour angiogenesis factor in human gliomas in vivo , 1992, Nature.

[48]  I. M. Neiman,et al.  [Inflammation and cancer]. , 1974, Patologicheskaia fiziologiia i eksperimental'naia terapiia.