Review Articles in 2012

This Review highlights the complexity and context-dependent roles of both β-catenin-dependent and β-catenin-independent WNT signalling pathways in cancer, as well as some of the ways in which WNT signalling might be targeted therapeutically.

Ceramide induces apoptosis, autophagy and cell cycle arrest and it is therefore often metabolized in tumour cells to suppress its function and promote proliferation. As also discussed in this Review, there are efforts to increase ceramide levels as a therapeutic avenue.

Protein arginine methylation has various effects on cell signalling — targeting signalling proteins as well as histones — and the protein arginine methyltransferases (PRMTs) are altered in various types of cancer, as discussed in this Review.

Pancreatic cancer has the poorest prognosis of any major cancer type. Familial pancreatic cancer registries are important for investigating the genetic aetiology of this devastating disease and provide a unique opportunity for laboratory, population and clinical research.

Oestrogen-related receptors (ERRs) have been shown to control vast gene networks that are involved in glycolysis, glutaminolysis, oxidative phosphorylation, nutrient sensing and biosynthesis pathways. This Review discusses these findings in the context of breast cancer and discusses whether targeting the ERRs for the development of cancer therapeutics is feasible.

Myelodysplastic syndromes (MDS) are malignant clonal disorders of haematopoietic stem cells and their microenvironment, affecting older individuals. Although emerging insights establish an association between molecular abnormalities (such as specific chromosomal abnormalities) and the phenotypic heterogeneity of MDS, as outlined in this Review the origin and progression of MDS remain enigmatic.

The DNA damage response (DDR) is often altered in tumour cells and this Review discusses the many strategies to target the pathways that comprise the DDR as single agents and in combination to produce synthetic lethality specifically in tumour cells.

Medulloblastoma has been the subject of numerous genomics and transcriptomics studies that have led to this disease being subclassified into various clinically meaningful groups and to advances in understanding the biology of these subgroups, with implications for treatment.

Based on previous successes and failures, this Review discusses potential future directions for cancer prevention that include the use of genetic, proteomic and other molecular approaches to identify pathways that could be modified during cancer initiation. The use of immunotherapies for cancer prevention is also discussed.

In recent years a new concept of immunogenic cell death (ICD) has emerged. In this Review, the authors discuss the role of endoplasmic reticulum (ER) stress and reactive oxygen species (ROS) in regulating the immunogenicity of dying cancer cells and how this might relate to therapeutic intervention.

Intracellular signalling cascades initiated by class III receptor tyrosine kinases (RTK-IIIs) and their cytokine ligands are implicated in a wide range of inflammatory disorders and cancers. This Review discusses recent crystal structure data of RTK-III ectodomains in complex with cognate cytokines and the insights that these provide in terms of RTK-III activation, evolution, pathology and new therapeutic approaches.

NAD is a vital molecule in all organisms and is a key component of both energy and signal transduction — processes that undergo crucial changes in cancer cells. NAD⁺-dependent signalling reactions involve the degradation of the molecule, so permanent nucleotide resynthesis through different biosynthetic pathways is crucial for incessant cancer cell proliferation. Is targeting of NAD metabolism a new therapeutic strategy for cancer treatment?

What have mitochondria ever done for us? This Review discusses why alterations in cellular processes that require mitochondria are essential for tumorigenesis.

Treating cancer patients with T cell-based therapies has shown some some promise in the clinic, but not all patients respond. There could be many reasons for this, some of which might be addressed by using the best possible antitumour T cell. What are the biological properties of such a cell and can we generate one?

Chromothripsis is an emerging phenomenon that results in chromosome rearrangements in tumour cells. This Review discusses the possible mechanisms underlying this process and its implications for cancer biology and in the clinic.

DNA damage response signalling pathways are often altered in tumours, which can affect their response to chemotherapy and targeted therapies. This Review discusses the mechanisms by which altered DNA damage responses elicit such therapy resistance.

NADPH oxidases of the NOX family are reactive oxygen species-generating enzymes that regulate redox-sensitive signalling pathways. In this Review, the authors discuss primary targets and redox-linked signalling systems that are influenced by NOX-derived ROS and the biological role that NOX oxidases might have in the aetiology of cancer.

Alterations to epigenetic regulators are a recently characterized class of oncogenic changes in myeloid malignancies. This Review discusses what these alterations mean for leukaemogenesis.

This Review discusses how microRNAs (miRNAs) are intricately involved in p53 signalling, from the regulation of p53 expression and activity to contributing to various tumour suppressor effector functions of p53. Evidence for the importance of these miRNAs from cancer-specific alterations, and the implications for diagnostics and therapeutics, are also considered.

Although chronic myeloid leukaemia (CML) can be treated with tyrosine kinase inhibitors (TKIs) against BCR-ABL1, cure is not achieved in most cases. This Review provides an update on resistance to TKIs, and discusses strategies to target BCR-ABL1-independent resistance, which may be necessary to eliminate CML stem cells and advanced disease.