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The identification in 1993 of inherited mutations in the von Hippel–Lindau (VHL) gene in families with VHL disease was a seminal finding. This and subsequent discoveries have given the VHLtumour suppressor gene a central role in our understanding of the mechanisms of cellular oxygen sensing and in the pathobiology of clear-cell renal cell carcinoma.
This Review discusses recent advances in the molecular characterization of bladder cancer, which has provided insights into pathogenesis and subgroups of bladder cancers with different prognosis.
Hyperactivation of phosphatidylinositol 3-kinase (PI3K) signalling cascades is one of the most common events in human cancers. This Review discusses recent advances in our knowledge of the roles of distinct PI3K isoforms in normal and oncogenic signalling, and the current state and future potential of targeting this pathway in the clinic.
The TYRO3, AXL and MERTK (TAM) family of receptor tyrosine kinases (RTKs) are overexpressed in tumour cells, promoting cell survival and chemoresistance. These RTKs also function in normal innate immune cells to promote an immunosuppressive tumour microenvironment. Thus, TAM RTKs are implicated as dual therapeutic targets in cancer.
Recent analyses of cancer genomes have revealed the occurrence of mutation patterns, which indicate their source. This Review discusses what we have learned, and what is yet to learn, from these data and how our current understanding of cancer mutations fits into our understanding of tumorigenesis and tumour progression.
The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that is best known for mediating the toxicity and tumour-promoting properties of dioxin. AHR levels are increased with constitutive nuclear localization in many tumours. How might AHR facilitate tumour progression, and can it be therapeutically modulated?
The Janus kinases (JAKs) are major activators of signal transducer and activator of transcription (STAT) proteins, and this signalling axis is crucial for cancer development in both tumour cells and the tumour microenvironment. This Review discusses the new roles of JAK–STAT signalling in promoting cancer through inflammation, obesity, stem cells and the pre-metastatic niche, and the potential therapeutic strategies that these roles can offer.
Reactive oxygen species (ROS) are generated through various mechanisms. Accumulating evidence indicates that these moieties have important roles in promoting tumorigenesis and tumour progression; modulating the redox balance could be a strategy in targeting cancer.
Survival for patients with metastatic or relapsed osteosarcoma has remained virtually unchanged during the past 30 years, and new therapeutic options are needed. This Review discusses normal bone biology relevant to osteosarcoma, including the immunobiology of bone, model systems for studying osteosarcoma, genetic and genomic studies on germline predisposition and tumour landscapes, and recent clinical trials.
Cancer cachexia is a multifactorial syndrome that affects many cancer patients and that leads to substantial weight loss, primarily from loss of skeletal muscle and body fat. This Opinion article focuses on the molecular mechanisms underlying cancer cachexia, in hopes that a better understanding of these might lead to improved therapeutic approaches.
Brownet al. argue that epigenetic heterogeneity leads to therapeutic resistance, such that bivalently marked gene promoters result in epigenetically poised gene expression that can become fixed by exposure to therapy. What are the opportunities to target this proposed mechanism of therapeutic resistance?
'Integrative oncology', also known as complementary and alternative medicine (CAM), is being increasingly accepted in cancer care and research. This Opinion article aims to define what is meant by CAM in cancer and argues that the vast majority of these treatments are supported by little, if any, scientific evidence. Furthermore, it asks the questions: is there any harm in these treatments, and are there any potential benefits?
There has recently been a flurry of publications on the molecular and genetic basis of diffuse high-grade glioma, a devastating paediatric tumour. In this Review, Jones and Baker integrate these findings to provide new insight into this disease. In particular, the unique selective pressures driving the paediatric disease along with their associated mutations, potential molecular mechanisms and how this information could be harnessed therapeutically, are discussed.
CUT-like homeobox 1 (CUX1) is a homeobox gene that is implicated in both tumour suppression and progression. What are the functions of the CUX1 protein, and how might the opposite roles of CUX1 in cancer protection and progression be explained?
Germline mutations inDICER1 can lead to DICER1 syndrome, which is characterized by the predisposition of various types of cancer in childhood and during early adulthood. Additionally, specific DICER1 mutations occur in tumours. This Review discusses germline and somatically-acquired DICER1mutations and their effects on tumorigenesis.
This Opinion article considers the current status of stem cell-based treatments for cancer, such as the optimization of technologies to manipulate and deploy stem cells to target cancerous cells. It addresses safety concerns and discusses how the most promising preclinical studies might be translated into the clinic.
The unfolded protein response (UPR) is an important pro-survival pathway that is often activated in tumour cells owing to endoplasmic reticulum stress that is caused by both intrinsic and extrinsic factors. Wang and Kaufman discuss the mechanisms of UPR activation in tumour cells, the importance of this pathway to cancer development and targeting strategies for therapeutic intervention.
Disseminated tumour cells that survive treatment may become dormant and their 'awakening' may be the source of metastases. This Review discusses the mechanisms and factors that regulate tumour dormancy, including the extracellular and stromal microenvironments, autophagy and epigenetics. The authors also discuss how this information could be used therapeutically for metastatic disease.
In this Opinion article, Buchheitet al. describe the cellular changes that regulate cell viability when cells become detached from the ECM. In particular, they discuss how cancer cells take advantage of these specific processes and how better understanding them will be instrumental in designing therapeutic strategies that aim to eliminate ECM-detached metastatic cells.
