Review Articles in 2013

p21-activated kinases (PAKs) have important roles in several oncogenic signalling pathways. How are PAKs activated in cancer, what are their key substrates, and how might small molecules against these enzymes best be developed and deployed for the treatment of cancer?

This Review discusses the elucidation of mechanisms whereby oestrogen drives both oestrogen receptor-α transactivation and receptor proteolysis, which might have important therapeutic implications not only for breast cancer but also for other hormone-regulated cancers.

This Review discusses recent evidence, particularly from mouse models, showing that some tetraspanin proteins have important roles in tumour initiation, promotion, metastasis and angiogenesis, and that they might therefore be valid therapeutic targets.

Potassium channels are transmembrane proteins that selectively facilitate the flow of potassium ions down an electrochemical gradient. Their roles in cell proliferation, angiogenesis and cell migration have only recently been assessed. Thus, the potential importance of these channels for tumour biology is only now becoming evident.

Mammalian basic HLH (helix–loop–helix)–PER–ARNT–SIM (bHLH–PAS) proteins are heterodimeric transcription factors. Recently determined structures of their PAS domains and successful small-molecule screening programmes are now providing new opportunities to discover selective agonists and antagonists directed against this multitasking family of transcription factors.

The roles of vascular endothelial growth factor (VEGF) in cancer go beyond effects on the vasculature. VEGF signalling in tumour cells, which is mediated by VEGF receptor tyrosine kinases and the neuropilins, contributes to many aspects of tumorigenesis, as highlighted in this Review.

The processes of intravasation and extravasation are thought to be crucial for cancer cell dissemination and metastasis. This Review describes how cancer cells cross the endothelial barrier, with a focus on the extravasation step.

Several studies have recently highlighted a crucial role for adenosine signalling in regulating various aspects of the cell-intrinsic and cell-extrinsic processes of cancer development. This Review critically discusses adenosine and its effects on immune, endothelial and cancer cells during the course of neoplastic disease.

The role of inflammation in tumorigenesis and tumour progression is increasingly coming into focus, and this Review discusses the current ideas about the mechanisms of inflammation-associated tumorigenesis and the association with the microbiota.

In this Review, the authors examine the aetiological, pathogenic and clinical features that are associated with cancers harbouring oncogenic fusion kinases, the clinical outcomes with targeted therapies, and strategies to discover additional kinases that are activated by chromosomal rearrangements in solid tumours.

The influence of the microenvironment on tumour progression is becoming clearer. This Review addresses the role of transforming growth factor-β in the regulation of components of the tumour microenvironment.

This Review discusses mechanisms of resistance to 'classical' cytotoxic chemotherapeutics and molecularly targeted therapies, which share many features. It is hoped that an improved understanding of the molecular basis of resistance will lead to rational drug combinations and predictive biomarkers.

Anaplastic lymphoma kinase (ALK) is commonly altered — through mutation, overexpression or translocation — in many types of cancer, but the role of ALK signalling in mammalian cells and tumours remains enigmatic. What can we learn from model systems? And what progress has been made in targeting this receptor tyrosine kinase?

Krüppel-like factor (KLF) transcriptional regulators have diverse functions in many cancer-relevant processes. This Review discusses the context-dependent roles for KLFs in different cancers and identifies key questions for the field.

Because of the increased production of acids, the altered metabolism of tumour cells renders them especially reliant on pH-regulatory systems that ensure that the intracellular pH does not decrease too much. This Review discusses the interplay among metabolism, hypoxia and pH regulation and whether pH-regulatory systems can be targeted for anticancer therapy.

The zebrafish has emerged as an important model system with which to investigate cancer, particularly for validating genomics data and for undertaking screens for oncogenes and drivers of tumour progression and metastasis. This Review outlines what we have learned and could still learn from cancer research using the zebrafish.

Endothelin 1 (ET1) is a secreted protein that can function through autocrine and paracrine signalling to modulate various properties of cancer cells and their microenvironment. This Review describes our latest understanding of the biological roles of ET1 in cancer and the results of clinical trials with drugs that target the ET1 signalling pathway.

Adoptive T cell therapy using engineered T cells to improve antitumour responses is showing promise for the treatment of haematological malignancies in particular. This Review discusses the strategies to engineer T cells and the progress that has been made with using gene-modified T cells to treat cancer patients.

Several cancers and genetic disorders are linked to defects in helicases that have roles in genome maintenance and stability. This Review discusses helicase-dependent DNA repair pathways and how targeting these might improve cancer treatments based on DNA-damaging chemotherapy or radiation.

Although the ABL1 kinase is well known as the fusion partner with BCR in chronic myeloid leukaemia (CML), roles for the ABL family (ABL1 and ABL2) in solid tumours are beginning to be uncovered. Small-molecule ABL inhibitors are crucial in CML therapy, but can these kinases be targeted for therapeutic benefit in other cancer types?