Wednesday, December 15, 2010

Hot off the presses! Dec 14 Cancer Cell

The Dec 14 issue of the Cancer Cell is now up on Pubget (About Cancer Cell): if you're at a subscribing institution, just click the link in the latest link at the home page. (Note you'll only be able to get all the PDFs in the issue if your institution subscribes to Pubget.)

Latest Articles Include:

  • BLIMP1 against Lymphoma: The Verdict Is Reached
    - Cancer Cells 18(6):537-539 (2010)
    BLIMP1, a master regulator of plasma-cell differentiation, is implicated in the pathogenesis of Activated B cell (ABC)-like Diffuse Large B cell Lymphoma (DLBCL). In this issue of Cancer Cell, Mandelbaum and colleagues and Calado and colleagues unequivocally demonstrate that BLIMP1 functions as a tumor suppressor and guardian of ABC-like DLBCL lymphomagenesis.
  • Partners in Crime: Genes within an Amplicon Collude to Globally Deregulate Chromatin in Lymphoma
    - Cancer Cells 18(6):539-541 (2010)
    In this issue of Cancer Cell, Rui et al. identify JAK2 and JMJDC2 as two contiguous, coamplified oncogenes in primary mediastinal B cell and Hodgkin lymphoma. Together, JAK2 and JMJD2C induce major changes in chromatin structure and gene expression. Targeting these proteins with small molecules represents a new avenue for therapy.
  • New Antibody to Stop Tumor Angiogenesis and Lymphatic Spread by Blocking Receptor Partnering
    - Cancer Cells 18(6):541-543 (2010)
    Tvorogov et al. (2010) describe in this issue of Cancer Cell an antibody that inhibits homodimerization of vascular endothelial growth factor receptor-3 (VEGFR-3) and its heterodimerization with VEGFR-2, but not ligand binding. The work provides mechanistic insights into receptor dimerization and an approach to suppress both angiogenesis and lymphangiogenesis.
  • The Ids Have It
    - Cancer Cells 18(6):543-545 (2010)
    In this issue of Cancer Cell, Anido et al. demonstrate that Id1 is the likely arbiter of divergent transforming growth factor-β (TGF-β) signaling in glioma-initiating cells (GICs) from different tumors. These findings hold both the promise and potential peril of therapeutic targeting of the TGF-β pathway.
  • A Malignant Oligarchy: Progenitors Govern the Behavior of Oligodendrogliomas
    - Cancer Cells 18(6):546-547 (2010)
    Recent studies have suggested that brain tumors arise from neural stem cells and are maintained by stem-like tumor-initiating cells (TICs). In this issue of Cancer Cell, Persson et al. report that oligodendrogliomas, unlike malignant astrocytomas, originate from—and are propagated by—cells that resemble oligodendrocyte progenitors.
  • ALK Inhibition for Non-Small Cell Lung Cancer: From Discovery to Therapy in Record Time
    - Cancer Cells 18(6):548-551 (2010)
    It was only 3 years ago that an acquired translocation of EML4 with ALK leading to the expression of an EML4-ALK oncoprotein in non-small cell lung cancer (NSCLC) was reported. Tumor cells expressing EML4-ALK are "addicted" to its continued function. Now, crizotinib, an oral ALK inhibitor, is demonstrated to provide dramatic clinical benefit with little toxicity in patients having such advanced NSCLC, and a mechanism of clinical resistance to crizotinib is identified. Such therapy "targeted" at oncogenic proteins provides "personalized" medicine and prompts genome-wide mutation analysis of human tumors to find other therapeutic targets.
  • Leukemic IDH1 and IDH2 Mutations Result in a Hypermethylation Phenotype, Disrupt TET2 Function, and Impair Hematopoietic Differentiation
    - Cancer Cells 18(6):553-567 (2010)
    Cancer-associated IDH mutations are characterized by neomorphic enzyme activity and resultant 2-hydroxyglutarate (2HG) production. Mutational and epigenetic profiling of a large acute myeloid leukemia (AML) patient cohort revealed that IDH1/2-mutant AMLs display global DNA hypermethylation and a specific hypermethylation signature. Furthermore, expression of 2HG-producing IDH alleles in cells induced global DNA hypermethylation. In the AML cohort, IDH1/2 mutations were mutually exclusive with mutations in the α-ketoglutarate-dependent enzyme TET2, and TET2 loss-of-function mutations were associated with similar epigenetic defects as IDH1/2 mutants. Consistent with these genetic and epigenetic data, expression of IDH mutants impaired TET2 catalytic function in cells. Finally, either expression of mutant IDH1/2 or Tet2 depletion impaired hematopoietic differentiation and increased stem/progenitor cell marker expression, suggesting a shared proleukemogenic effect.
  • BLIMP1 Is a Tumor Suppressor Gene Frequently Disrupted in Activated B Cell-like Diffuse Large B Cell Lymphoma
    - Cancer Cells 18(6):568-579 (2010)
    Diffuse large B cell lymphoma (DLBCL) is a heterogeneous disease composed of at least two distinct subtypes: germinal center B cell-like (GCB) and activated B cell-like (ABC) DLBCL. These phenotypic subtypes segregate with largely unique genetic lesions, suggesting the involvement of different pathogenetic mechanisms. In this report we show that the BLIMP1/PRDM1 gene is inactivated by multiple mechanisms, including homozygous deletions, truncating or missense mutations, and transcriptional repression by constitutively active BCL6, in 53% of ABC-DLBCL. In vivo, conditional deletion of Blimp1 in mouse B cells promotes the development of lymphoproliferative disorders recapitulating critical features of the human ABC-DLBCL. These results demonstrate that BLIMP1 is a bona fide tumor-suppressor gene whose loss contributes to lymphomagenesis by blocking plasma cell differentiation.
  • Constitutive Canonical NF-κB Activation Cooperates with Disruption of BLIMP1 in the Pathogenesis of Activated B Cell-like Diffuse Large Cell Lymphoma
    - Cancer Cells 18(6):580-589 (2010)
    Diffuse large B cell lymphoma (DLBCL) comprises disease entities with distinct genetic profiles, including germinal center B cell (GCB)-like and activated B cell (ABC)-like DLBCLs. Major differences between these two subtypes include genetic aberrations leading to constitutive NF-κB activation and interference with terminal B cell differentiation through BLIMP1 inactivation, observed in ABC- but not GCB-DLBCL. Using conditional gain-of-function and/or loss-of-function mutagenesis in the mouse, we show that constitutive activation of the canonical NF-κB pathway cooperates with disruption of BLIMP1 in the development of a lymphoma that resembles human ABC-DLBCL. Our work suggests that both NF-κB signaling, as an oncogenic event, and BLIMP1, as a tumor suppressor, play causal roles in the pathogenesis of ABC-DLBCL.
  • Cooperative Epigenetic Modulation by Cancer Amplicon Genes
    - Cancer Cells 18(6):590-605 (2010)
    Chromosome band 9p24 is frequently amplified in primary mediastinal B cell lymphoma (PMBL) and Hodgkin lymphoma (HL). To identify oncogenes in this amplicon, we screened an RNA interference library targeting amplicon genes and thereby identified JAK2 and the histone demethylase JMJD2C as essential genes in these lymphomas. Inhibition of JAK2 and JMJD2C cooperated in killing these lymphomas by decreasing tyrosine 41 phosphorylation and increasing lysine 9 trimethylation of histone H3, promoting heterochromatin formation. MYC, a major target of JAK2-mediated histone phosphorylation, was silenced after JAK2 and JMJD2C inhibition, with a corresponding increase in repressive chromatin. Hence, JAK2 and JMJD2C cooperatively remodel the PMBL and HL epigenome, offering a mechanistic rationale for the development of JAK2 and JMJD2C inhibitors in these diseases.
  • β-Catenin Mediates the Establishment and Drug Resistance of MLL Leukemic Stem Cells
    - Cancer Cells 18(6):606-618 (2010)
    Identification of molecular pathways essential for cancer stem cells is critical for understanding the underlying biology and designing effective cancer therapeutics. Here, we demonstrated that β-catenin was activated during development of MLL leukemic stem cells (LSCs). Suppression of β-catenin reversed LSCs to a pre-LSC-like stage and significantly reduced the growth of human MLL leukemic cells. Conditional deletion of β-catenin completely abolished the oncogenic potential of MLL-transformed cells. In addition, established MLL LSCs that have acquired resistance against GSK3 inhibitors could be resensitized by suppression of β-catenin expression. These results unveil previously unrecognized multifaceted functions of β-catenin in the establishment and drug-resistant properties of MLL stem cells, highlighting it as a potential therapeutic target for an important subset of AMLs.
  • Loss of ATM/Chk2/p53 Pathway Components Accelerates Tumor Development and Contributes to Radiation Resistance in Gliomas
    - Cancer Cells 18(6):619-629 (2010)
    Maintenance of genomic integrity is essential for adult tissue homeostasis and defects in the DNA-damage response (DDR) machinery are linked to numerous pathologies including cancer. Here, we present evidence that the DDR exerts tumor suppressor activity in gliomas. We show that genes encoding components of the DDR pathway are frequently altered in human gliomas and that loss of elements of the ATM/Chk2/p53 cascade accelerates tumor formation in a glioma mouse model. We demonstrate that Chk2 is required for glioma response to ionizing radiation in vivo and is necessary for DNA-damage checkpoints in the neuronal stem cell compartment. Finally, we observed that the DDR is constitutively activated in a subset of human GBMs, and such activation correlates with regions of hypoxia.
  • Effective Suppression of Vascular Network Formation by Combination of Antibodies Blocking VEGFR Ligand Binding and Receptor Dimerization
    - Cancer Cells 18(6):630-640 (2010)
    Antibodies that block vascular endothelial growth factor (VEGF) have become an integral part of antiangiogenic tumor therapy, and antibodies targeting other VEGFs and receptors (VEGFRs) are in clinical trials. Typically receptor-blocking antibodies are targeted to the VEGFR ligand-binding site. Here we describe a monoclonal antibody that inhibits VEGFR-3 homodimer and VEGFR-3/VEGFR-2 heterodimer formation, signal transduction, as well as ligand-induced migration and sprouting of microvascular endothelial cells. Importantly, we show that combined use of antibodies blocking ligand binding and receptor dimerization improves VEGFR inhibition and results in stronger inhibition of endothelial sprouting and vascular network formation in vivo. These results suggest that receptor dimerization inhibitors could be used to enhance antiangiogenic activity of antibodies blocking ligand binding in tumor therapy.
  • Targeting Mitotic Exit Leads to Tumor Regression In Vivo: Modulation by Cdk1, Mastl, and the PP2A/B55α,δ Phosphatase
    - Cancer Cells 18(6):641-654 (2010)
    Targeting mitotic exit has been recently proposed as a relevant therapeutic approach against cancer. By using genetically engineered mice, we show that the APC/C cofactor Cdc20 is essential for anaphase onset in vivo in embryonic or adult cells, including progenitor/stem cells. Ablation of Cdc20 results in efficient regression of aggressive tumors, whereas current mitotic drugs display limited effects. Yet, Cdc20 null cells can exit from mitosis upon inactivation of Cdk1 and the kinase Mastl (Greatwall). This mitotic exit depends on the activity of PP2A phosphatase complexes containing B55α or B55δ regulatory subunits. These data illustrate the relevance of critical players of mitotic exit in mammals and their implications in the balance between cell death and mitotic exit in tumor cells.
  • TGF-β Receptor Inhibitors Target the CD44high/Id1high Glioma-Initiating Cell Population in Human Glioblastoma
    - Cancer Cells 18(6):655-668 (2010)
    Glioma-initiating cells (GICs), also called glioma stem cells, are responsible for tumor initiation, relapse, and therapeutic resistance. Here, we show that TGF-β inhibitors, currently under clinical development, target the GIC compartment in human glioblastoma (GBM) patients. Using patient-derived specimens, we have determined the gene responses to TGF-β inhibition, which include inhibitors of DNA-binding protein (Id)-1 and -3 transcription factors. We have identified a cell population enriched for GICs that expresses high levels of CD44 and Id1 and tend to be located in a perivascular niche. The inhibition of the TGF-β pathway decreases the CD44high/Id1high GIC population through the repression of Id1 and Id3 levels, therefore inhibiting the capacity of cells to initiate tumors. High CD44 and Id1 levels confer poor prognosis in GBM patients.
  • Non-Stem Cell Origin for Oligodendroglioma
    - Cancer Cells 18(6):669-682 (2010)
    Malignant astrocytic brain tumors are among the most lethal cancers. Quiescent and therapy-resistant neural stem cell (NSC)-like cells in astrocytomas are likely to contribute to poor outcome. Malignant oligodendroglial brain tumors, in contrast, are therapy sensitive. Using magnetic resonance imaging (MRI) and detailed developmental analyses, we demonstrated that murine oligodendroglioma cells show characteristics of oligodendrocyte progenitor cells (OPCs) and are therapy sensitive, and that OPC rather than NSC markers enriched for tumor formation. MRI of human oligodendroglioma also suggested a white matter (WM) origin, with markers for OPCs rather than NSCs similarly enriching for tumor formation. Our results suggest that oligodendroglioma cells show hallmarks of OPCs, and that a progenitor rather than a NSC origin underlies improved prognosis in patients with this tumor.
  • Acquired Resistance to BRAF Inhibitors Mediated by a RAF Kinase Switch in Melanoma Can Be Overcome by Cotargeting MEK and IGF-1R/PI3K
    - Cancer Cells 18(6):683-695 (2010)
    BRAF is an attractive target for melanoma drug development. However, resistance to BRAF inhibitors is a significant clinical challenge. We describe a model of resistance to BRAF inhibitors developed by chronic treatment of BRAFV600E melanoma cells with the BRAF inhibitor SB-590885; these cells are cross-resistant to other BRAF-selective inhibitors. Resistance involves flexible switching among the three RAF isoforms, underscoring the ability of melanoma cells to adapt to pharmacological challenges. IGF-1R/PI3K signaling was enhanced in resistant melanomas, and combined treatment with IGF-1R/PI3K and MEK inhibitors induced death of BRAF inhibitor-resistant cells. Increased IGF-1R and pAKT levels in a post-relapse human tumor sample are consistent with a role for IGF-1R/PI3K-dependent survival in the development of resistance to BRAF inhibitors.
  • CD4+ T Cells Contribute to the Remodeling of the Microenvironment Required for Sustained Tumor Regression upon Oncogene Inactivation
    - Cancer Cells 18(6):696 (2010)

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