Hot off the presses! Dec 08 Cancer Cell

The Dec 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:

• Very CIN-ful: Whole Chromosome Instability Promotes Tumor Suppressor Loss of Heterozygosity
  Sotillo R Schvartzman JM Benezra R - Cancer Cell 16(6):451-452 (2009)
  Mechanisms by which whole chromosome instability lead to tumorigenesis have eluded the cancer research field. In this issue of Cancer Cell, Baker et al. show that CIN induced by a defective mitotic checkpoint, under certain genetic and tissue contexts, leads to accelerated loss of heterozygosity of a tumor suppressor gene.
• A Stiff Blow from the Stroma: Collagen Crosslinking Drives Tumor Progression
  Ng MR Brugge JS - Cancer Cell 16(6):455-457 (2009)
  Matrix stiffness is an important microenvironmental cue that regulates cell growth, motility, and differentiation. In a recent Cell report, Weaver and colleagues implicate lysyl-oxidase-mediated collagen crosslinking as a contributor to tumor matrix stiffening, which leads to enhanced integrin signaling and invasive behavior in tumors.
• Steroid Hormone Receptors in Prostate Cancer: A Hard Habit to Break?
  Attard G Cooper CS de Bono JS - Cancer Cell 16(6):458-462 (2009)
  The clinical data from abiraterone acetate and MDV-3100 confirm continued androgen receptor (AR) addiction in a significant proportion of castration-resistant prostate cancers (CRPC). However, patients nearly invariably progress with a rise in prostate-specific antigen, suggesting resumption of transcription of hormone-regulated genes. If CRPC remains addicted to steroid receptor signaling, including, but not exclusive, to AR, how does reactivation occur? Or if cancers lose this addiction, do they remain driven by the same oncogenic mechanisms? The future development of therapeutics for CRPC should be informed by an understanding of the mechanisms underlying disease progression following treatment with these novel agents.
• Somatic Mutations in p85α Promote Tumorigenesis through Class IA PI3K Activation
  Jaiswal BS Janakiraman V Kljavin NM Chaudhuri S Stern HM Wang W Kan Z Dbouk HA Peters BA Waring P Dela Vega T Kenski DM Bowman KK Lorenzo M Li H Wu J Modrusan Z Stinson J Eby M Yue P Kaminker JS de Sauvage FJ Backer JM Seshagiri S - Cancer Cell 16(6):463-474 (2009)
  Members of the mammalian phosphoinositide-3-OH kinase (PI3K) family of proteins are critical regulators of various cellular process including cell survival, growth, proliferation, and motility. Oncogenic activating mutations in the p110α catalytic subunit of the heterodimeric p110/p85 PI3K enzyme are frequent in human cancers. Here we show the presence of frequent mutations in p85α in colon cancer, a majority of which occurs in the inter-Src homology-2 (iSH2) domain. These mutations uncouple and retain p85α's p110-stabilizing activity, while abrogating its p110-inhibitory activity. The p85α mutants promote cell survival, AKT activation, anchorage-independent cell growth, and oncogenesis in a p110-dependent manner.
• Whole Chromosome Instability Caused by Bub1 Insufficiency Drives Tumorigenesis through Tumor Suppressor Gene Loss of Heterozygosity
  Baker DJ Jin F Jeganathan KB van Deursen JM - Cancer Cell 16(6):475-486 (2009)
  Genetic alterations that promote chromosome missegregation have been proposed to drive tumorigenesis through loss of whole chromosomes containing key tumor suppressor genes. To test this unproven idea, we bred Bub1 mutant mice that inaccurately segregate their chromosomes onto p53+/−, ApcMin/+, Rb+/−, or Pten+/− backgrounds. Bub1 insufficiency predisposed p53+/− mice to thymic lymphomas and ApcMin/+ mice to colonic tumors. These tumors consistently lacked the nonmutated tumor suppressor allele but had gained a copy of the mutant allele. In contrast, Bub1 insufficiency had no impact on tumorigenesis in Rb+/− mice and inhibited prostatic intraepithelial neoplasia formation in Pten+/− mice. Thus, Bub1 insufficiency can drive tumor formation through tumor suppressor gene loss of heterozygosity, but only in restricted genetic and cellular contexts.
• miR-221&222 Regulate TRAIL Resistance and Enhance Tumorigenicity through PTEN and TIMP3 Downregulation
  Garofalo M Di Leva G Romano G Nuovo G Suh SS Ngankeu A Taccioli C Pichiorri F Alder H Secchiero P Gasparini P Gonelli A Costinean S Acunzo M Condorelli G Croce CM - Cancer Cell 16(6):498-509 (2009)
  Lung and liver cancers are among the most deadly types of cancer. Despite improvements in treatment over the past few decades, patient survival remains poor, underlining the need for development of targeted therapies. MicroRNAs represent a class of small RNAs frequently deregulated in human malignancies. We now report that miR-221&222 are overexpressed in aggressive non-small cell lung cancer and hepatocarcinoma cells, as compared with less invasive and/or normal lung and liver cells. We show that miR-221&222, by targeting PTEN and TIMP3 tumor suppressors, induce TRAIL resistance and enhance cellular migration through the activation of the AKT pathway and metallopeptidases. Finally, we demonstrate that the MET oncogene is involved in miR-221&222 activation through the c-Jun transcription factor.
• Tissue-Penetrating Delivery of Compounds and Nanoparticles into Tumors
  Sugahara KN Teesalu T Karmali PP Kotamraju VR Agemy L Girard OM Hanahan D Mattrey RF Ruoslahti E - Cancer Cell 16(6):510-520 (2009)
  Poor penetration of drugs into tumors is a major obstacle in tumor treatment. We describe a strategy for peptide-mediated delivery of compounds deep into the tumor parenchyma that uses a tumor-homing peptide, iRGD (CRGDK/RGPD/EC). Intravenously injected compounds coupled to iRGD bound to tumor vessels and spread into the extravascular tumor parenchyma, whereas conventional RGD peptides only delivered the cargo to the blood vessels. iRGD homes to tumors through a three-step process: the RGD motif mediates binding to αv integrins on tumor endothelium and a proteolytic cleavage then exposes a binding motif for neuropilin-1, which mediates penetration into tissue and cells. Conjugation to iRGD significantly improved the sensitivity of tumor-imaging agents and enhanced the activity of an antitumor drug.
• A Gene Signature Predictive for Outcome in Advanced Ovarian Cancer Identifies a Survival Factor: Microfibril-Associated Glycoprotein 2
  Mok SC Bonome T Vathipadiekal V Bell A Johnson ME Wong KK Park DC Hao K Yip DK Donninger H Ozbun L Samimi G Brady J Randonovich M Pise-Masison CA Barrett JC Wong WH Welch WR Berkowitz RS Birrer MJ - Cancer Cell 16(6):521-532 (2009)
  Advanced stage papillary serous tumors of the ovary are responsible for the majority of ovarian cancer deaths, yet the molecular determinants modulating patient survival are poorly characterized. Here, we identify and validate a prognostic gene expression signature correlating with survival in a series of microdissected serous ovarian tumors. Independent evaluation confirmed the association of a prognostic gene microfibril-associated glycoprotein 2 (MAGP2) with poor prognosis, whereas in vitro mechanistic analyses demonstrated its ability to prolong tumor cell survival and stimulate endothelial cell motility and survival via the αVβ3 integrin receptor. Increased MAGP2 expression correlated with microvessel density suggesting a proangiogenic role in vivo. Thus, MAGP2 may serve as a survival-associated target.
• Reviewer List for 2009
  - Cancer Cell 16(6):I-III (2009)