Review Articles in 2010

The inhibitor of apoptosis (IAP) proteins were first investigated because of their capacity to inhibit programmed cell death in response to a number of physiological stimuli. Their disruption is also evident in many types of human cancer. As small pharmacological inhibitors of IAPs enter clinical trials, this Review examines what we now know about the function of a subset of family members — cIAP1, cIAP2 and XIAP.

Increasing evidence indicates that misregulation of histone modifications can contribute to cancer. This Review summarizes how misreading, miswriting and mis-erasing histone methylation marks are involved in tumorigenesis and progression, by deregulating gene expression and perturbing cellular identity.

High-risk human papillomaviruses are considered the causative agents of most cervical cancers. The modifications by the human papillomavirus E6 and E7 oncoproteins of cell cycle progression, telomere maintenance, apoptosis and chromosomal stability and their fundamental role in transformation are discussed in this Review.

Genomic genetically engineered mouse models (GEMMs) have provided a wealth of information about the genes and factors involved in tumour progression. However, various limitations exist for such models, particularly for preclinical drug development. So, what improvements can the non-germline GEMMs offer?

There is increasing evidence that sphingosine 1-phosphate (S1P), S1P receptors, sphingosine kinases, S1P phosphatases and S1P lyase are involved in cancer development and progression. This Review summarizes current research findings and discusses the potential for new therapeutics.

Cartilage tumours range from benign lesions, such as enchondromas and osteochondromas, to malignant chondrosarcoma. Cytogenetic studies and mouse models are beginning to identify genes and signalling pathways that have roles in tumour progression and potential new therapeutic approaches.

Transforming growth factor-β (TGFβ) signalling regulates tumour progression by cell-autonomous signalling pathways and through tumour–stromal interactions, and can have either a tumour-suppressing or tumour-promoting function, depending on cellular context. Such inherent complexity of TGFβ signalling results in arduous, but promising, assignments for developing therapeutic strategies.

Helicobacter pyloricauses gastric adenocarcinoma in a minority of infected individuals. What have we learned about bacterial and host-specific factors that lead to malignancy, and what canH. pyloritell us about inflammatory carcinomas that develop beyond the gastric niche?

The presence of single nucleotide polymorphisms in microRNA genes, their processing machinery and target binding sites might affect cancer risk, treatment efficacy and patient prognosis. This evolving field of cancer biology is discussed in this Review.

There have been substantial advances in the understanding of the basic biology and pathogenesis of malignant glioma and medulloblastoma over the past two decades. This Review summarizes these developments in the context of the molecular classification of these types of brain cancer and discusses the implications for the design of new treatment regimens.

Key roles in cancer development have been established for PI3K and PTEN — enzymes that regulate the levels of phosphatidylinositol-3,4,5-trisphosphate, but several other phosphoinositide-modifying enzymes have been implicated in the generation and progression of tumours. New insights into the mechanisms and the extent of their involvement in cancer are summarized in this Review.

Recent reports have identified the ubiquitin-editing enzyme A20 as a crucial tumour suppressor in various lymphomas. This Review analyses how deregulation of ubiquitylation in the NF-κB signalling pathway can promote tumorigenesis.

Effects on both global protein synthesis and selective translation of specific mRNAs can contribute to cancer development and progression. How are components of the translation machinery altered in cancer, and can these be targeted therapeutically?

Tumour-derived cell lines are an important model for the discovery and development of new anticancer drugs. The recent development of large panels of cell lines and high-throughput technologies has revitalized this field, and this Review discusses how these tools can be used to screen anticancer agents.

This Review discusses the progress made with developing drugs that specifically target the altered metabolic pathways of tumours and suggests additional targets that might also be beneficial.

Many proteases are regulated by phosphorylation, and many kinases are regulated by proteolytic cleavage. This Review examines kinase–protease interactions and their functional effects in cancer in depth, revealing the enormous diversity and complexity of this crosstalk.

Accumulating evidence implicates the deregulation of Eph–ephrin signalling in cancer pathogenesis. Bidirectional signalling and context-dependent effects allow the Eph–ephrin system to have complex and contrasting effects on tumours. There is still much to be learned about this system in cancer, but it is nevertheless emerging as a therapeutic target.

Eicosanoids, including prostaglandins and leukotrienes, are biologically active lipids that have been implicated in inflammation and cancer. This Review highlights the roles of eicosanoids in tumours and their microenvironment, and how their signalling pathways might be exploited to develop more effective cancer chemopreventive and/or therapeutic agents.

Microtubules are dynamic structures composed of α–β-tubulin heterodimers that are important targets for tubulin-binding agents such as paclitaxel. Mutation or aberrant expression of specific β-tubulin isotypes and changes to microtubule-regulating proteins are associated with resistance to these drugs. Understanding the molecular mechanisms that mediate this resistance will be vital to improve the efficacy of these agents.

Fibroblast growth factors (FGFs) and their receptors have been shown to drive tumorigenesis and tumour progression. However, FGF signalling can also be tumour suppressive, and understanding the mechanisms that underlie these context-specific effects will be important to rationally target FGF signalling for therapeutic benefit.