Models of cancer come in a variety of forms, from cancer cell lines in culture to genetically modified mice. In between are a host of organisms that also contribute to our understanding of this disease. Yeast, for example, have added much to our knowledge of the cell cycle and the maintenance of cell polarity, whereas egg extracts from Xenopus laevishave helped our comprehension of biochemical pathways and protein modifications essential for normal cellular function. Work onCaenorhabditis eleganswas crucial for our grasp of the genetic pathway that regulates programmed cell death, and research in Drosophila melanogaster has identified several pathways that are deregulated during cancer formation, including the Hippo tumour suppressor pathway. Whether results are generated by cell lines, yeast, mouse orthotopic tumour models or zebrafish the cumulative information from these models should help us to understand in greater detail the subtleties of cancer formation.

The deregulated expression of genes and non–protein coding RNAs, which occur through both genetic mechanisms (such as mutation and translocation) and epigenetic mechanisms (such as promoter methylation and histone modifications) are known to promote tumorigenesis and tumour progression. Our knowledge of the mechanisms through which such changes occur and the resulting effects on tumour biology and clinical outcome is increasing rapidly. This series of articles highlights this recent progress and discusses the implications for cancer diagnosis and treatment.

Hypoxia can influence tumour formation, progression and therapy in several ways. It has, among other things, been linked to driving angiogenesis, therapeutic resistance and pathological changes to metabolic pathways. This Nature Reviews CancerCollection on Hypoxia and metabolism includes a selection of recent Reviews, Perspectives and Research Highlights that provide insight into the roles of these processes in tumour biology and therapy.

To celebrate the past 30 years of research on p53 this Focus issue of specially-commissioned articles reflects the history and emerging directions that will be important for future research on this multi-talented protein.

Beginning in the July 2009 issue, Nature Reviews Cancerwill be publishing a series of articles that take a look at different aspects of therapeutic resistance. Resistance to therapy — chemotherapy or radiotherapy — is an increasing problem in the care of patients with cancer. Numerous culprits have been identified, including environmental adaptations to therapy, aberrant regulation of drug transporters and signalling feedback loops that bypass targeted therapies. As discussed in the articles in this series, multi–targeted drugs, improved understanding of feedback regulation, pathway crosstalk and resistance mechanisms, as well as predictors of response all aim to overcome this significant challenge.

The resurgence of interest in the underlying processes of metastasis has led to significant new insights and translational developments. The specially commissioned articles in this Focus on Migration and metastasis discuss the new and re-emerging models and pathways that have been redefined with regard to their role in metastasis and metastasis suppression.

Although not cloned in 1971, the RBtumour suppressor gene is famous for being the subject of the Knudson two hit hypothesis. Much has been discovered about RB since then, but how it functions as an tumour suppressor remains enigmatic. Aside from its regulation of the G1 phase of the cell cycle, in particular by suppressing the function of the E2F family of transcription factors, there is increasing evidence that RB regulates other important cellular pathways. Indeed, it is now No. longer possible to cover the potential functions of RB and E2F in one bite-size review. Instead, we have commissioned a short series of articles that discuss some of newer strings that have been assigned to the RB bow and some of the questions that still need to be answered.

Although anti-angiogenesis agents targeting vascular endothelial growth factor (VEGF) pathways are already in clinical use and can effectively treat some cancers, there is a continued need for development of new angiogenesis inhibitors to circumvent resistance or reduce toxicity. Articles in this Focus issue describe some of the emerging targets for new anti-angiogenic therapies in cancer and also discuss our evolving knowledge of VEGF inhibitors based on results from the clinic.

Senescence and its potential contribution to cancer has often been overlooked, perhaps because it is easier to assess, both in vitro and in vivo, the net contribution of cell loss through death rather than permanent cell cycle arrest. However, many recent discoveries, aided in part by the availability of established markers of senescent cells in vivo, have rekindled interest in senescence as a tumour suppressive mechanism. This series of articles on senescence highlights the latest progress, and whether our increasing understanding of the mechanisms that trigger senescence might be useful for the development of innovative cancer therapies that enable patients to live long term with stable disease.

MicroRNAs (miRNAs) — an abundant class of small non–protein–coding regulators of gene expression — play an important role in tumorigenesis and, depending on their targets, can function as tumour suppressors or oncogenes. Crucially, miRNA–expression profiling of human tumours has identified signatures associated with diagnosis, staging, progression, prognosis and response to treatment.

Here we present a series of specially commissioned articles that discuss the key issues and our current knowledge of MYC and cancer. Since the isolation of the MYC oncogene in the early 1980's, the concepts that try to explain how this transcription factor contributes to tumorigenesis are numerous and encompass many fields. And yet, new ideas about MYC–dependent responses and how these might be involved in tumorigenesis are still emerging as the repertoire of signalling pathways that are induced downstream of MYC activation expand. In addition, key concepts implicit in the consideration of how MYC might function as an oncogene are also likely to be relevant to other oncogenes and transcription factors, and may have therapeutic relevance.

Throughout 2008, a series of specially commissioned articles that examine hypoxia and metabolism in tumour biology will be published in Nature Reviews Cancer. Although hypoxia is not a new phenomenon, we now have a much greater understanding of the molecular links between hypoxic conditions and tumour development. Apart from driving angiogenesis, hypoxia is also linked with changes in cellular metabolism, an area that has become a hot topic in cancer research. A greater understanding of these closely related tumorigenic changes should prove fruitful in the pursuit of more effective cancer drugs.