Review Articles in 2011

Recent studies have identified frequent inactivating mutations in different SWI/SNF subunits in several types of cancer, highlighting the tumour suppressor roles of these chromatin remodellers. This Review discusses the current knowledge regarding inactivating mutations, and silencing, of SWI/SNF subunits in cancer, the molecular mechanisms of their tumour suppressor functions and possibilities for therapeutic intervention in SWI/SNF-mutant cancers.

Research into basic developmental biology has frequently yielded insights into cancer biology. This is particularly true for the Hedgehog (HH) pathway, and both naturally occurring and synthetic inhibitors of HH signalling show great promise. However, it remains unclear how many cancers will ultimately benefit from these new, molecularly targeted therapies.

Hypoxia is common in developing and advanced tumours and could therefore provide a means for drug selectivity. As discussed in this Review, this can be achieved either by using prodrugs that are activated in hypoxic regions, or by directly targeting hypoxia-induced signalling pathways that confer survival to tumour cells.

When cancer metastasizes to bone, considerable pain and deregulated bone remodelling occurs, greatly diminishing the possibility of cure. Understanding how metastasizing tumour cells mobilize and sculpt the bone microenvironment to enhance tumour growth and promote bone invasion has uncovered new therapeutic opportunities.

The long-term risks from new radiotherapy treatments, such as particle therapy, have not yet been determined and there is a need to try and develop risk assessments based on our current knowledge of radiation-induced carcinogenesis. Which information can we use to produce the best models?

DNA, mRNA and microRNA are released and circulate in the blood of cancer patients. This Review discusses the potential clinical utility of cell-free nucleic acids as blood biomarkers.

The calpains are a conserved family of cysteine proteinases that catalyse the controlled proteolysis of many specific substrates that are involved in proliferation, apoptosis and migration. Calpain expression is altered during tumorigenesis and can influence the response to cancer therapies, indicating a need for new calpain inhibitors.

Otto Warburg has contributed important data and hypotheses to the fields of cancer research and metabolism, but what did he actually find and what conclusions did he draw? This Review looks at the life and research of Otto Warburg and places his work in the context of our current understanding of metabolism and hypoxia in cancer.

The Notch family of receptors activate a complex web of cancer-relevant signalling pathways, and activating mutations inNOTCH1are common drivers of T cell acute lymphoblastic leukaemia (T-ALL). Despite this oncogenic role of NOTCH1 in T-ALL, mutations in Notch genes are rare in solid cancers. This Review discusses the growing evidence that deregulation of Notch signalling can indeed have a major role in the development of various solid tumours, and the oncogenic versus tumour suppressive roles of Notch signalling are highly context dependent.

The incidence of metastasis to the brain is apparently rising in cancer patients and threatens to limit the gains that have been made by new systemic treatments. As discussed in this Review, translational research that aims to improve the outcome for patients with brain metastases needs to be multi-disciplinary, marrying advanced chemistry, blood–brain barrier pharmacokinetics, neurocognitive testing and radiation biology with metastasis biology.

PTENis one of the most frequently inactivated tumour suppressor genes in cancer, and approximately 80% of patients with Cowden syndrome have mutations inPTEN. This Review discusses the different types of PTEN-mutant tumours that occur in Cowden syndrome and the mouse models that have been engineered to study them.

Radiotherapy is the most common treatment for cancer patients, and so methods to improve responses are an important challenge. This Review discusses strategies to modulate tumour responses to radiotherapy with radiosensitizers and how normal tissue responses to ionizing radiation can be repressed with radioprotectors.

Recent genome-wide association studies have implicated six gene loci in the development of testicular germ cell tumours (TGCTs). The function of the proteins encoded by genes at these loci bridge our understanding between the pathways involved in primordial germ cell physiology, male germ cell development and the molecular pathology of TGCTs.

The unique ability of human pluripotent stem cells to self-renew and to differentiate into cells of the three germ layers makes them an invaluable tool for the future of regenerative medicine and tumorigenic research. It was assumed that human induced pluripotent stem cells (HiPSCs) would behave like their embryonic counterparts in respect to their tumorigenicity, but a rapidly accumulating body of evidence suggests that there are important differences.

CD44 has been implicated as a cancer-initiating cell (CIC; also known as a cancer stem cell) marker in several malignancies of haematopoietic and epithelial origin. Is this a fortuitous coincidence owing to the widespread expression of the molecule or is CD44 expression advantageous?

Telomeres protect chromosomes from degradation and are therefore essential for ensuring genomic stability. These heterochromatic structures are bound by the shelterin complex, which regulates the activity of telomerase at the ends of chromosomes. This Review analyses the role of these telomeric proteins in cancer and ageing through modulating telomere length and protection, as well as through their 'extracurriculum' activities as gene expression regulators by binding to non-telomeric sites.

Netrin 1 and members of the Slit family and their receptors are deregulated in a large proportion of human cancers, suggesting that they could be tumour suppressor genes or oncogenes. Evidence for and against these functions is discussed, along with recent data that these ligand–receptor pairs could be promising targets for personalized anticancer therapies.

Invasive cell migration requires the formation of various structures, such as invadopodia and pseudopodia, which require actin assembly. Studies of the mechanisms of various actin nucleation factors that are involved in actin assembly might ultimately provide new treatments for invasive and metastatic disease.

DNA polymerases have various roles from DNA replication to tolerating DNA damage through a process known as translesion DNA synthesis. This Review discusses the function of the DNA polymerase family and their possible roles in cancer.

Fundamental differences in the regulation of central metabolic pathways exist between tumours and normal tissue. This Review discusses how the Warburg effect is still applicable to our view of cancer metabolism and new advances in understanding beyond this hypothesis, including regulating anapleurosis and the redox balance.