Hot off the presses! Jun 02 Cancer Cell

The Jun 02 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:

• Telomere Uncapping, Chromosomes, and Carcinomas
  Batista LF Artandi SE - Cancer Cell 15(6):455-457 (2009)
  Data from mouse models and from human cancers have supported the idea that telomere shortening leads to chromosomal instability and epithelial carcinogenesis. In this issue of Cancer Cell, Else et al. demonstrate that telomere uncapping—altering a protein that protects chromosome ends without shortening telomeres—also results in epithelial cancers.
• Mammary Tumorigenesis through LPA Receptor Signaling
  Jonkers J Moolenaar WH - Cancer Cell 15(6):457-459 (2009)
  Lysophosphatidic acid (LPA) is a lipid growth factor that is produced by an extracellular phospholipase, termed autotaxin (ATX), and acts via G protein-coupled receptors. In this issue of Cancer Cell, Liu et al. show that transgenic overexpression of ATX or LPA receptors leads to invasive and metastatic mammary cancer.
• Bringing H2AX into the Angiogenesis Family
  Rankin EB Giaccia AJ Hammond EM - Cancer Cell 15(6):459-461 (2009)
  The cell's ability to sense and respond to DNA damage is critical to maintain homeostasis and prevent the development of cancer. Paradoxically, Economopoulou et al. recently reported that a DNA damage response protein, H2AX, promotes tumor growth and angiogenesis.
• Development of Androgen Receptor Antagonists with Promising Activity in Castration-Resistant Prostate Cancer
  Shen HC Balk SP - Cancer Cell 15(6):461-463 (2009)
  Androgen receptor (AR) continues to play a central role in prostate cancers that relapse after androgen deprivation therapy, but these tumors are refractory to available AR antagonists. In a recent issue of Science, Tran et al. describe an antagonist that prevents AR recruitment to chromatin and shows efficacy in relapsed prostate cancer.
• Genetic p53 Deficiency Partially Rescues the Adrenocortical Dysplasia Phenotype at the Expense of Increased Tumorigenesis
  Else T Trovato A Kim AC Wu Y Ferguson DO Kuick RD Lucas PC Hammer GD - Cancer Cell 15(6):465-476 (2009)
  Telomere dysfunction and shortening induce chromosomal instability and tumorigenesis. In this study, we analyze the adrenocortical dysplasia (acd) mouse, harboring a mutation in Tpp1/Acd. Additional loss of p53 dramatically rescues the acd phenotype in an organ-specific manner, including skin hyperpigmentation and adrenal morphology, but not germ cell atrophy. Survival to weaning age is significantly increased in Acdacd/acd p53−/− mice. On the contrary, p53−/− and p53+/− mice with the Acdacd/acd genotype show a decreased tumor-free survival, compared with Acd+/+ mice. Tumors from Acdacd/acd p53+/− mice show a striking switch from the classic spectrum of p53−/− mice toward carcinomas. The acd mouse model provides further support for an in vivo role of telomere deprotection in tumorigenesis.
• Modeling Inducible Human Tissue Neoplasia Identifies an Extracellular Matrix Interaction Network Involved in Cancer Progression
  Reuter JA Ortiz-Urda S Kretz M Garcia J Scholl FA Pasmooij AM Cassarino D Chang HY Khavari PA - Cancer Cell 15(6):477-488 (2009)
  To elucidate mechanisms of cancer progression, we generated inducible human neoplasia in three-dimensionally intact epithelial tissue. Gene expression profiling of both epithelia and stroma at specific time points during tumor progression revealed sequential enrichment of genes mediating discrete biologic functions in each tissue compartment. A core cancer progression signature was distilled using the increased signaling specificity of downstream oncogene effectors and subjected to network modeling. Network topology predicted that tumor development depends on specific extracellular matrix-interacting network hubs. Blockade of one such hub, the β1 integrin subunit, disrupted network gene expression and attenuated tumorigenesis in vivo. Thus, integrating network modeling and temporal gene expression analysis of inducible human neoplasia provides an approach to prioritize and characterize genes functioning in cancer progression.
• A Gene Expression Signature Associated with "K-Ras Addiction" Reveals Regulators of EMT and Tumor Cell Survival
  Singh A Greninger P Rhodes D Koopman L Violette S Bardeesy N Settleman J - Cancer Cell 15(6):489-500 (2009)
  K-ras mutations occur frequently in epithelial cancers. Using short hairpin RNAs to deplete K-Ras in lung and pancreatic cancer cell lines harboring K-ras mutations, two classes were identified—lines that do or do not require K-Ras to maintain viability. Comparing these two classes of cancer cells revealed a gene expression signature in K-Ras-dependent cells, associated with a well-differentiated epithelial phenotype, which was also seen in primary tumors. Several of these genes encode pharmacologically tractable proteins, such as Syk and Ron kinases and integrin β6, depletion of which induces epithelial-mesenchymal transformation (EMT) and apoptosis specifically in K-Ras-dependent cells. These findings indicate that epithelial differentiation and tumor cell viability are associated, and that EMT regulators in "K-Ras-addicted" cancers represent candidate therapeutic targets.
• Hypoxia-Inducible Factors Regulate Tumorigenic Capacity of Glioma Stem Cells
  Li Z Bao S Wu Q Wang H Eyler C Sathornsumetee S Shi Q Cao Y Lathia J McLendon RE Hjelmeland AB Rich JN - Cancer Cell 15(6):501-513 (2009)
  Glioblastomas are lethal cancers characterized by florid angiogenesis promoted in part by glioma stem cells (GSCs). Because hypoxia regulates angiogenesis, we examined hypoxic responses in GSCs. We now demonstrate that hypoxia-inducible factor HIF2α and multiple HIF-regulated genes are preferentially expressed in GSCs in comparison to non-stem tumor cells and normal neural progenitors. In tumor specimens, HIF2α colocalizes with cancer stem cell markers. Targeting HIFs in GSCs inhibits self-renewal, proliferation, and survival in vitro, and attenuates tumor initiation potential of GSCs in vivo. Analysis of a molecular database reveals that HIF2A expression correlates with poor glioma patient survival. Our results demonstrate that GSCs differentially respond to hypoxia with distinct HIF induction patterns, and HIF2α might represent a promising target for antiglioblastoma therapies.
• Expression of Mutant p53 Proteins Implicates a Lineage Relationship between Neural Stem Cells and Malignant Astrocytic Glioma in a Murine Model
  Wang Y Yang J Zheng H Tomasek GJ Zhang P McKeever PE Lee EY Zhu Y - Cancer Cell 15(6):514-526 (2009)
  Recent studies have identified genes and core pathways that are altered in human glioblastoma. However, the mechanisms by which alterations of these glioblastoma genes singly and cooperatively transform brain cells remain poorly understood. Further, the cell of origin of glioblastoma is largely elusive. By targeting a p53 in-frame deletion mutation to the brain, we show that p53 deficiency provides no significant growth advantage to adult brain cells, but appears to induce pleiotropic accumulation of cooperative oncogenic alterations driving gliomagenesis. Our data show that accumulation of a detectable level of mutant p53 proteins occurs first in neural stem cells in the subventricular zone (SVZ) and that subsequent expansion of mutant p53-expressing Olig2+ transit-amplifying progenitor-like cells in the SVZ-associated areas initiates glioma formation.
• Tumor Vasculature Is Regulated by PHD2-Mediated Angiogenesis and Bone Marrow-Derived Cell Recruitment
  Chan DA Kawahara TL Sutphin PD Chang HY Chi JT Giaccia AJ - Cancer Cell 15(6):527-538 (2009)
  Sustained angiogenesis, through either local sprouting (angiogenesis) or the recruitment of bone marrow-derived cells (BMDCs) (vasculogenesis), is essential to the development of a tumor. How BMDCs are recruited to the tumor and their contribution to the tumor vasculature is poorly understood. Here, we demonstrate that both IL-8 and angiogenin contribute to the complementary pathways of angiogenesis and BMDC mobilization to increase tumor growth. These two factors are regulated by PHD2 in a HIF-independent but NF-κB-dependent manner. PHD2 levels are decreased in human cancers, compared with corresponding normal tissue, and correlate with an increase in mature blood vessels. Thus, PHD2 plays a critical role in regulating tumor angiogenesis.
• Expression of Autotaxin and Lysophosphatidic Acid Receptors Increases Mammary Tumorigenesis, Invasion, and Metastases
  Liu S Umezu-Goto M Murph M Lu Y Liu W Zhang F Yu S Stephens LC Cui X Murrow G Coombes K Muller W Hung MC Perou CM Lee AV Fang X Mills GB - Cancer Cell 15(6):539-550 (2009)
  Lysophosphatidic acid (LPA) acts through high-affinity G protein-coupled receptors to mediate a plethora of physiological and pathological activities associated with tumorigenesis. LPA receptors and autotaxin (ATX/LysoPLD), the primary enzyme producing LPA, are aberrantly expressed in multiple cancer lineages. However, the role of ATX and LPA receptors in the initiation and progression of breast cancer has not been evaluated. We demonstrate that expression of ATX or each edg family LPA receptor in mammary epithelium of transgenic mice is sufficient to induce a high frequency of late-onset, estrogen receptor (ER)-positive, invasive, and metastatic mammary cancer. Thus, ATX and LPA receptors can contribute to the initiation and progression of breast cancer.