Hot off the presses! Jan 01 Nat Rev Cancer

The Jan 01 issue of the Nat Rev Cancer is now up on Pubget (About Nat Rev Cancer): 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:

• Cancer genomics: Finding a rare variant | PDF (765 KB)
  - Nat Rev Cancer 12(1):1 (2012)
  Familial melanoma has been linked to mutations in cyclin-dependent kinase inhibitor 2A (CDKN2A) and CDK4, but these two genes account for only a minority of genetic risk. Two studies reported in Nature have now identified a germline mutation in microphthalmia-associated transcription factor (MITF) that predisposes to familial melanoma, as well as to sporadic melanoma and renal cell carcinoma (RCC).
• Epigenetics: Worth another look? | PDF (358 KB)
  - Nat Rev Cancer 12(1):2 (2012)
  A paper that was published recently in Cancer Discovery indicates that patients with non-small-cell lung cancer (NSCLC) with tumours that have a specific subset of methylated genes might benefit from combined treatment with a low-dose DNA methyltransferase inhibitor and a histone deacetylase inhibitor (HDACI).
• Microenvironment: Protective surroundings | PDF (425 KB)
  - Nat Rev Cancer 12(1):2 (2012)
  Johanna Joyce and colleagues investigated whether changes to the tumour microenvironment that promote growth — as occurs during tumour progression — might influence the recovery of tumours, and thus the overall response to chemotherapy.
• Biomarkers: Major mathematical hurdles for biomarker-based screening | PDF (202 KB)
  - Nat Rev Cancer 12(1):3 (2012)
  A new mathematical model suggests that the successful use of blood-based biomarkers for the early detection of premalignant tumours might require methodological improvements of unanticipated magnitude.
• Breast cancer: Staking a claim | PDF (318 KB)
  - Nat Rev Cancer 12(1):4 (2012)
  The increased transcriptional activity of oestrogen receptor-α (ERα) is involved in the development of approximately 70% of breast cancers. Mathieu Lupien and colleagues investigated the function of pioneer factors — sequence-specific DNA binding proteins that can remodel chromatin to enable transcription — in ERα-mediated transcription.
• Metastasis: Signalling in transit | PDF (217 KB)
  - Nat Rev Cancer 12(1):4 (2012)
  The microenvironment of a primary tumour has been recognized as an important player in cancer progression, but whether circulating tumour cells respond to additional metastatic signals during their transit through the vasculature is unclear. Given the high concentrations of growth factors and cytokines that are contained in platelets, Labelle, Begum and Hynes proposed that, in addition to their known roles in promoting cell adhesion and protecting tumour cells from death, platelets might provide pro-metastatic signals to circulating tumour cells.
• Therapeutics: Opening the door to a new class of proteasome inhibitors | PDF (254 KB)
  - Nat Rev Cancer 12(1):5 (2012)
  The first proteasome-targeted drug, bortezomib, was approved in 2003 for the treatment of multiple myeloma and this validated the 20S proteolytic subunit of the proteasome as an anticancer target. Now, reporting in Nature Medicine, Linder and colleagues present a small-molecule inhibitor of proteasomal deubiquitylases that induces tumour cell apoptosis, potentially paving the way for the development of a new class of proteasome inhibitors.
• Senescence: Tumorigenesis under surveillance | PDF (225 KB)
  - Nat Rev Cancer 12(1):6 (2012)
  Senescent cells are known to secrete various chemokines and cytokines that can trigger their clearance by innate immune cells. However, the extent to which this immune surveillance system is involved in tumour suppression is poorly characterized.
• Genetics: IDH mosaicism in enchondromatosis syndromes | PDF (218 KB)
  - Nat Rev Cancer 12(1):6 (2012)
  Mutation of certain hotspot arginine residues in the isocitrate dehydrogenases IDH1 and IDH2 has been found in cartilaginous tumours, gliomas and acute myeloid leukaemia (AML). These tumour types also occur in patients with Maffucci syndrome and Ollier disease, and two groups have investigated whether mutations in IDH1 and IDH2 are evident in these patients.
• Metastasis: Awakening a sleeping giant | PDF (99 KB)
  - Nat Rev Cancer 12(1):6 (2012)
  Metastatic recurrence of breast cancer years after successful treatment of the primary tumour is an important clinical problem, but the molecular events that control the activation of dormant micrometastases are poorly understood. Using a mouse model that recapitulates the transition from indolent micrometastases to overt bone metastasis, Lu et al.
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• HIF1α and HIF2α: sibling rivalry in hypoxic tumour growth and progression
  - Nat Rev Cancer 12(1):9 (2012)
  Hypoxia-inducible factors (HIFs) are broadly expressed in human cancers, and HIF1α and HIF2α were previously suspected to promote tumour progression through largely overlapping functions. However, this relatively simple model has now been challenged in light of recent data from various approaches that reveal unique and sometimes opposing activities of these HIFα isoforms in both normal physiology and disease. These effects are mediated in part through the regulation of unique target genes, as well as through direct and indirect interactions with important oncoproteins and tumour suppressors, including MYC and p53. As HIF inhibitors are currently undergoing clinical evaluation as cancer therapeutics, a more thorough understanding of the unique roles performed by HIF1α and HIF2α in human neoplasia is warranted.
• Epithelial cell polarity, stem cells and cancer
  - Nat Rev Cancer 12(1):23 (2012)
  After years of extensive scientific discovery much has been learned about the networks that regulate epithelial homeostasis. Loss of expression or functional activity of cell adhesion and cell polarity proteins (including the PAR, crumbs (CRB) and scribble (SCRIB) complexes) is intricately related to advanced stages of tumour progression and invasiveness. But the key roles of these proteins in crosstalk with the Hippo and liver kinase B1 (LKB1)–AMPK pathways and in epithelial function and proliferation indicate that they may also be associated with the early stages of tumorigenesis. For example, deregulation of adhesion and polarity proteins can cause misoriented cell divisions and increased self-renewal of adult epithelial stem cells. In this Review, we highlight some advances in the understanding of how loss of epithelial cell polarity contributes to tumorigenesis.
• Treating metastatic cancer with nanotechnology
  - Nat Rev Cancer 12(1):39 (2012)
  Metastasis accounts for the vast majority of cancer deaths. The unique challenges for treating metastases include their small size, high multiplicity and dispersion to diverse organ environments. Nanoparticles have many potential benefits for diagnosing and treating metastatic cancer, including the ability to transport complex molecular cargoes to the major sites of metastasis, such as the lungs, liver and lymph nodes, as well as targeting to specific cell populations within these organs. This Review highlights the research, opportunities and challenges for integrating engineering sciences with cancer biology and medicine to develop nanotechnology-based tools for treating metastatic disease.
• Safe harbours for the integration of new DNA in the human genome
  - Nat Rev Cancer 12(1):51 (2012)
  DNA and the host genome limit the reliability and safety of transgene integration for therapeutic cell engineering and other applications. Although targeted gene delivery has made considerable progress, the question of where to insert foreign sequences in the human genome to maximize safety and efficacy has received little attention. In this Opinion article, we discuss 'genomic safe harbours' — chromosomal locations where therapeutic transgenes can integrate and function in a predictable manner without perturbing endogenous gene activity and promoting cancer.
• Programmed cell removal: a new obstacle in the road to developing cancer
  - Nat Rev Cancer 12(1):58 (2012)
  The development of cancer involves mechanisms by which aberrant cells overcome normal regulatory pathways that limit their numbers and their migration. The evasion of programmed cell death is one of several key early events that need to be overcome in the progression from normal cellular homeostasis to malignant transformation. Recently, we provided evidence in mouse and human cancers that successful cancer clones must also overcome programmed cell removal. In this Opinion article, we explore the role of programmed cell removal in both normal and neoplastic cells, and we place this pathway in the context of the initiation of programmed cell death.
• BRCA1 and BRCA2: different roles in a common pathway of genome protection
  - Nat Rev Cancer 12(1):68 (2012)
  The proteins encoded by the two major breast cancer susceptibility genes, BRCA1 and BRCA2, work in a common pathway of genome protection. However, the two proteins work at different stages in the DNA damage response (DDR) and in DNA repair. BRCA1 is a pleiotropic DDR protein that functions in both checkpoint activation and DNA repair, whereas BRCA2 is a mediator of the core mechanism of homologous recombination. The links between the two proteins are not well understood, but they must exist to explain the marked similarity of human cancer susceptibility that arises with germline mutations in these genes. As discussed here, the proteins work in concert to protect the genome from double-strand DNA damage during DNA replication.
• Regulatory RNA: Layer by layer
  - Nat Rev Cancer 12(1):78 (2012)
  Nature Reviews Cancer11, 830 (2011) In the above article, the name of an author was misspelt in the text and should have been Pavel Sumazin. This has been corrected online.