Hot off the presses! Mar 08 Cancer Cell

The Mar 08 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:

• Glioma Models: New GEMMs Add "Class" with Genomic and Expression Correlations
  - Cancer Cells 19(3):295-297 (2011)
  Malignant gliomas are characterized by accumulated aberrations affecting TP53, PTEN, and RB1 signaling. In this issue, Chow et al. discover that combinatorial loss of these tumor suppressors in mice induces gliomas with unexpected degrees of similarity to human pathologic, genomic, and expression subclasses recently revealed by large-scale genomic studies.
• Escaping Anoikis through ROS: ANGPTL4 Controls Integrin Signaling through Nox1
  - Cancer Cells 19(3):297-299 (2011)
  Reactive oxygen species (ROS) mediate various cell fate decisions in normal and transformed cells. In this issue of Cancer Cell, Zhu et al. demonstrate the ability of ANGPTL4 to engage integrin-dependent survival signals by activation of the NADPH oxidase Nox1, thus mimicking anchorage conditions and bypassing anoikis by controlling ROS.
• SIRT3 Controls Cancer Metabolic Reprogramming by Regulating ROS and HIF
  - Cancer Cells 19(3):299-300 (2011)
  In this issue of Cancer Cell, Finley and coworkers report that the genetic loss of the deacetylase SIRT3 leads to metabolic reprogramming toward glycolysis. This shift is mediated by an increase in cellular reactive oxygen species (ROS) generation that amplifies HIF-α stabilization and HIF-dependent gene expression, thereby driving the tumor phenotype.
• Disruptive Events in the Life of Prostate Cancer
  - Cancer Cells 19(3):301-303 (2011)
  Two recent reports in Nature provide evidence for increasingly complex "disruptive" molecular alterations that occur during prostate cancer progression. They shed light on the intricacy of genetic changes that modulate PTEN's control over the phosphoinositide 3-kinase pathway and prostate cancer progression, and identify new potential biomarkers and therapeutic targets.
• Cooperativity within and among Pten, p53, and Rb Pathways Induces High-Grade Astrocytoma in Adult Brain
  - Cancer Cells 19(3):305-316 (2011)
  Mutations in the PTEN, TP53, and RB1 pathways are obligate events in the pathogenesis of human glioblastomas. We induced various combinations of deletions in these tumor suppressors in astrocytes and neural precursors in mature mice, resulting in astrocytomas ranging from grade III to grade IV (glioblastoma). There was selection for mutation of multiple genes within a pathway, shown by somatic amplifications of genes in the PI3K or Rb pathway in tumors in which Pten or Rb deletion was an initiating event. Despite multiple mutations within PI3K and Rb pathways, elevated Mapk activation was not consistent. Gene expression profiling revealed striking similarities to subclasses of human diffuse astrocytoma. Astrocytomas were found within and outside of proliferative niches in the adult brain.
• URI Is an Oncogene Amplified in Ovarian Cancer Cells and Is Required for Their Survival
  - Cancer Cells 19(3):317-332 (2011)
  Abrogation of negative feedback control represents a fundamental requirement for aberrantly activated signaling pathways to promote malignant transformation and resistance to therapy. Here we identify URI, which encodes a mitochondrial inhibitor of PP1γ and PP1γ-mediated feedback inhibition of S6K1-BAD survival signaling, as an oncogene amplified and overexpressed in ovarian cancer cell lines and human ovarian carcinomas. URI is an "addicting" oncogene selectively required for the survival of ovarian cancer cells with increased URI copy number. By constitutively detaining PP1γ in inactive complexes, URI sustains S6K1 survival signaling under growth factor–limiting conditions and mediates resistance of cells to cisplatin. Thus, oncogenic activation of URI defines an important mechanism for activating mitochondrial S6K1-BAD signaling and promoting cell survival through disabling PP1γ-dependent negative feedback inhibition.
• Matrix Metalloproteinase-2 Conditions Human Dendritic Cells to Prime Inflammatory TH2 Cells via an IL-12- and OX40L-Dependent Pathway
  - Cancer Cells 19(3):333-346 (2011)
  Matrix metalloproteinase-2 (MMP-2) is a proteolytic enzyme degrading the extracellular matrix and overexpressed by many tumors. Here, we documented the presence of MMP-2-specific CD4+ T cells in tumor-infiltrating lymphocytes (TILs) from melanoma patients. Strikingly, MMP-2-specific CD4+ T cells displayed an inflammatory TH2 profile, i.e., mainly secreting TNF-α, IL-4, and IL-13 and expressing GATA-3. Furthermore, MMP-2-conditioned dendritic cells (DCs) primed naïve CD4+ T cells to differentiate into an inflammatory TH2 phenotype through OX40L expression and inhibition of IL-12p70 production. MMP-2 degrades the type I IFN receptor, thereby preventing STAT1 phosphorylation, which is necessary for IL-12p35 production. Active MMP-2, therefore, acts as an endogenous type 2 "conditioner" and may play a role in the observed prevalence of detrimental type 2 responses in melanoma.
• Identification of a Therapeutic Strategy Targeting Amplified FGF19 in Liver Cancer by Oncogenomic Screening
  - Cancer Cells 19(3):347-358 (2011)
  We screened 124 genes that are amplified in human hepatocellular carcinoma (HCC) using a mouse hepatoblast model and identified 18 tumor-promoting genes, including CCND1 and its neighbor on 11q13.3, FGF19. Although it is widely assumed that CCND1 is the main driving oncogene of this common amplicon (15% frequency in HCC), both forward-transformation assays and RNAi-mediated inhibition in human HCC cells established that FGF19 is an equally important driver gene in HCC. Furthermore, clonal growth and tumorigenicity of HCC cells harboring the 11q13.3 amplicon were selectively inhibited by RNAi-mediated knockdown of CCND1 or FGF19, as well as by an anti-FGF19 antibody. These results show that 11q13.3 amplification could be an effective biomarker for patients most likely to respond to anti-FGF19 therapy.
• The Central Nervous System-Restricted Transcription Factor Olig2 Opposes p53 Responses to Genotoxic Damage in Neural Progenitors and Malignant Glioma
  - Cancer Cells 19(3):359-371 (2011)
  High-grade gliomas are notoriously insensitive to radiation and genotoxic drugs. Paradoxically, the p53 gene is structurally intact in the majority of these tumors. Resistance to genotoxic modalities in p53-positive gliomas is generally attributed to attenuation of p53 functions by mutations of other components within the p53 signaling axis, such as p14Arf, MDM2, and ATM, but this explanation is not entirely satisfactory. We show here that the central nervous system (CNS)-restricted transcription factor Olig2 affects a key posttranslational modification of p53 in both normal and malignant neural progenitors and thereby antagonizes the interaction of p53 with promoter elements of multiple target genes. In the absence of Olig2 function, even attenuated levels of p53 are adequate for biological responses to genotoxic damage.
• Twist1-Induced Invadopodia Formation Promotes Tumor Metastasis
  - Cancer Cells 19(3):372-386 (2011)
  The Twist1 transcription factor is known to promote tumor metastasis and induce Epithelial-Mesenchymal Transition (EMT). Here, we report that Twist1 is capable of promoting the formation of invadopodia, specialized membrane protrusions for extracellular matrix degradation. Twist1 induces PDGFRα expression, which in turn activates Src, to promote invadopodia formation. We show that Twist1 and PDGFRα are central mediators of invadopodia formation in response to various EMT-inducing signals. Induction of PDGFRα and invadopodia is essential for Twist1 to promote tumor metastasis. Consistent with PDGFRα being a direct transcriptional target of Twist1, coexpression of Twist1 and PDGFRα predicts poor survival in breast tumor patients. Therefore, invadopodia-mediated matrix degradation is a key function of Twist1 in promoting tumor metastasis.
• CD44 Variant Regulates Redox Status in Cancer Cells by Stabilizing the xCT Subunit of System xc− and Thereby Promotes Tumor Growth
  - Cancer Cells 19(3):387-400 (2011)
  CD44 is an adhesion molecule expressed in cancer stem-like cells. Here, we show that a CD44 variant (CD44v) interacts with xCT, a glutamate-cystine transporter, and controls the intracellular level of reduced glutathione (GSH). Human gastrointestinal cancer cells with a high level of CD44 expression showed an enhanced capacity for GSH synthesis and defense against reactive oxygen species (ROS). Ablation of CD44 induced loss of xCT from the cell surface and suppressed tumor growth in a transgenic mouse model of gastric cancer. It also induced activation of p38MAPK, a downstream target of ROS, and expression of the gene for the cell cycle inhibitor p21CIP1/WAF1. These findings establish a function for CD44v in regulation of ROS defense and tumor growth.
• Angiopoietin-like 4 Protein Elevates the Prosurvival Intracellular O2−:H2O2 Ratio and Confers Anoikis Resistance to Tumors
  - Cancer Cells 19(3):401-415 (2011)
  Cancer is a leading cause of death worldwide. Tumor cells exploit various signaling pathways to promote their growth and metastasis. To our knowledge, the role of angiopoietin-like 4 protein (ANGPTL4) in cancer remains undefined. Here, we found that elevated ANGPTL4 expression is widespread in tumors, and its suppression impairs tumor growth associated with enhanced apoptosis. Tumor-derived ANGPTL4 interacts with integrins to stimulate NADPH oxidase-dependent production of O2−. A high ratio of O2−:H2O2 oxidizes/activates Src, triggering the PI3K/PKBα and ERK prosurvival pathways to confer anoikis resistance, thus promoting tumor growth. ANGPTL4 deficiency results in diminished O2− production and a reduced O2−:H2O2 ratio, creating a cellular environment conducive to apoptosis. ANGPTL4 is an important redox player in cancer and a potential therapeutic target.
• SIRT3 Opposes Reprogramming of Cancer Cell Metabolism through HIF1α Destabilization
  - Cancer Cells 19(3):416-428 (2011)
  Tumor cells exhibit aberrant metabolism characterized by high glycolysis even in the presence of oxygen. This metabolic reprogramming, known as the Warburg effect, provides tumor cells with the substrates required for biomass generation. Here, we show that the mitochondrial NAD-dependent deacetylase SIRT3 is a crucial regulator of the Warburg effect. Mechanistically, SIRT3 mediates metabolic reprogramming by destabilizing hypoxia-inducible factor-1α (HIF1α), a transcription factor that controls glycolytic gene expression. SIRT3 loss increases reactive oxygen species production, leading to HIF1α stabilization. SIRT3 expression is reduced in human breast cancers, and its loss correlates with the upregulation of HIF1α target genes. Finally, we find that SIRT3 overexpression represses glycolysis and proliferation in breast cancer cells, providing a metabolic mechanism for tumor suppression.