Reviews & Analysis

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.

Evolutionary life history theory posits that some organisms reproduce rapidly whereas others invest more resources in survival. This framework might help us to understand the diversity of phenotypes that are displayed by tumour cells, including stem cell-like phenotypes, and could have important clinical implications.

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.

There is an emerging association between the microbiota and carcinogenesis. How might the microbiota modulate tumorigenesis, and what do we need to understand to more firmly conclude that the microbiome causes cancer?

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 Opinion article outlines the roles of vesicle trafficking pathways in various phenotypes shown by cancer cells, especially loss of polarity and invasion, and argues that although these proteins are not drivers of transformation, they are integral to maintaining neoplastic phenotypes.

Myeloid-derived suppressor cells (MDSCs) remain steeped in mystery and controversy — how do we identify them? How are they recruited to the tumour microenvironment? How do they suppress antitumour immunity? This Timeline article discusses the discovery of MDSCs and what we know now — and need to know in the future — about the role of MDSCs in cancer biology.

What can we learn about cancer stem cells and tumour tissue hierarchy from what we know about stem cells? Read this Opinion article to find out how our knowledge of normal stem cells applies to cancer stem cells in solid tumours.

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.