The phenomenon of field cancerization (the existence of histologically abnormal tissue beyond a neoplastic area that predisposes to tumour formation) was described in the 1950s on the basis of analyses of squamous cell carcinomas (SCCs). Field cancerization is primarily attributed to changes in the epithelium, but whether changes in mesenchymal cells might also have a primary role in the establishment of afield effect is not clear.
Early detection represents one of the most promising approaches to reducing the growing cancer burden. It already has a key role in the management of cervical and breast cancer, and is likely to become more important in the control of colorectal, prostate and lung cancer. Early-detection research has recently been revitalized by the advent of novel molecular technologies that can identify cellular changes at the level of the genome or proteome, but how can we harness these new technologies to develop effective and practical screening tests?
Epidemiological studies indicate that vitamin D insufficiency could have an aetiological role in various human cancers. Preclinical research indicates that the active metabolite of vitamin D, 1alpha,25(OH)2D3, also known as calcitriol, or vitamin D analogues might have potential as anticancer agents because their administration has antiproliferative effects, can activate apoptotic pathways and inhibit angiogenesis. In addition, 1alpha,25(OH)2D3 potentiates the anticancer effects of many cytotoxic and antiproliferative anticancer agents. Here, we outline the epidemiological, preclinical and clinical studies that support the development of 1alpha,25(OH)2D3 and vitamin D analogues as preventative and therapeutic anticancer agents.
The normal prostate and early-stage prostate cancers depend on androgens for growth and survival, and androgen ablation therapy causes them to regress. Cancers that are not cured by surgery eventually become androgen independent, rendering anti-androgen therapy ineffective. But how does androgen independence arise? We predict that understanding the pathways that lead to the development of androgen-independent prostate cancer will pave the way to effective therapies for these, at present, untreatable cancers.
The stepwise progression from an early dysplastic lesion to full-blown metastatic malignancy is associated with increases in genomic instability. Mitotic chromosomal instability - the inability to faithfully segregate equal chromosome complements to two daughter cells during mitosis - is a widespread phenomenon in solid tumours that is thought to serve as the fuel for tumorigenic progression. How chromosome instability (CIN) arises in tumours and what consequences it has are still, however, hotly debated issues. Here we review the recent literature with an emphasis on models that recapitulate observations from human disease.
Tumour cells acquire the ability to proliferate uncontrollably, resist apoptosis, sustain angiogenesis and evade immune surveillance. STAT proteins — especially STAT3 and STAT5 — regulate all of these processes and are persistently activated in a surprisingly large number of human cancers. Consequently, STAT proteins are emerging — unexpectedly — as ideal targets for cancer therapy.
The advent of molecularly targeted drug discovery has facilitated the identification of a new generation of anti-mitotic therapies that target proteins with specific functions in mitosis. The exquisite selectivity for mitosis and the distinct ways in which these new agents interfere with mitosis provides the potential to not only overcome certain limitations of current tubulin-targeted anti-mitotic drugs, but to expand the scope of clinical efficacy that those drugs have established. The development of these new anti-mitotic drugs as targeted therapies faces significant challenges; nevertheless, these potential therapies also serve as unique tools to dissect the molecular mechanisms of the mitotic-checkpoint response.
The normal functioning of p53 is a potent barrier to cancer. Tumour-associated mutations in TP53, typically single nucleotide substitutions in the coding sequence, are a hallmark of most human cancers and cause dramatic defects in p53 function. By contrast, only a small fraction, if any, of the >200 naturally occurring sequence variations (single nucleotide polymorphisms, SNPs) of TP53 in human populations are expected to cause measurable perturbation of p53 function. Polymorphisms in the TP53 locus that might have cancer-related phenotypical manifestations are the subject of this Review. Polymorphic variants of other genes in the p53 pathway, such as MDM2, which might have biological consequences either individually or in combination with p53 variants are also discussed.
DNA vaccination has suddenly become a favoured strategy for inducing immunity. The molecular precision offered by gene-based vaccines, together with the facility to include additional genes to direct and amplify immunity, has always been attractive. However, the apparent failure to translate operational success in preclinical models to the clinic, for reasons that are now rather obvious, reduced initial enthusiasm. Recently, novel delivery systems, especially electroporation, have overcome this translational block. Here, we assess the development, current performance and potential of DNA vaccines for the treatment of cancer.
Cells within tissues are continuously exposed to physical forces including hydrostatic pressure, shear stress, and compression and tension forces. Cells dynamically adapt to force by modifying their behaviour and remodelling their microenvironment. They also sense these forces through mechanoreceptors and respond by exerting reciprocal actomyosin- and cytoskeletal-dependent cell-generated force by a process termed 'mechanoreciprocity'. Loss of mechanoreciprocity has been shown to promote the progression of disease, including cancer. Moreover, the mechanical properties of a tissue contribute to disease progression, compromise treatment and might also alter cancer risk. Thus, the changing force that cells experience needs to be considered when trying to understand the complex nature of tumorigenesis.
Mitosis is the most dramatic--and potentially dangerous--event in the cell cycle, as sister chromatids are irreversibly segregated to daughter cells. Defects in the checkpoints that normally maintain the fidelity of this process can lead to chromosomal instability (CIN) and cancer. However, CIN--a driving force of tumorigenesis--could be the cancer cell's ultimate vulnerability. An important goal is to identify novel anticancer compounds that directly target the mitotic errors at the heart of CIN.
Transient megakaryoblastic leukaemia is found in 10% of newborns with Down syndrome, characterized by constitutional trisomy 21. Although in most cases the leukaemic cells disappear spontaneously after the first months of life, irreversible acute megakaryoblastic leukaemia develops in 20% of these individuals within 4 years. The leukaemic cells typically harbour somatic mutations of the gene encoding GATA1, an essential transcriptional regulator of normal megakaryocytic differentiation. Leukaemia that specifically arises in the context of constitutional trisomy 21 and somatic GATA1 mutations is a unique biological model of the incremental process of leukaemic transformation.
Hypoxia occurs in the majority of tumours, promoting angiogenesis, metastasis and resistance to therapy. Responses to hypoxia are orchestrated in part through activation of the hypoxia-inducible factor family of transcription factors (HIFs). Recently, two additional O(2)-sensitive signalling pathways have also been implicated: signalling through the mammalian target of rapamycin (mTOR) kinase and signalling through activation of the unfolded protein response (UPR). Although they are activated independently, growing evidence suggests that HIF-, mTOR- and UPR-dependent responses to hypoxia act in an integrated way, influencing each other and common downstream pathways that affect gene expression, metabolism, cell survival, tumorigenesis and tumour growth.
Krüppel-like factors are transcriptional regulators that influence several cellular functions, including proliferation. Recent studies have shown that one family member, KLF4, can function both as a tumour suppressor and an oncogene. The ability of KLF4 to affect the levels of expression of the cell-cycle regulator p21 seems to be involved, in that this protein might function as a switch that determines the outcome of KLF4 signalling. Is this role of p21 restricted to KLF4, or does p21 represent a nodal point for signals from multiple other factors with opposing functions in cancer?
Over the past decade, the identification of cancer-associated factors has been a subject of primary interest not only for understanding the basic mechanisms of tumorigenesis but also for discovering the associated therapeutic targets. However, aminoacyl-tRNA synthetases (ARSs) have been overlooked, mostly because many assumed that they were simply 'housekeepers' that were involved in protein synthesis. Mammalian ARSs have evolved many additional domains that are not necessarily linked to their catalytic activities. With these domains, they interact with diverse regulatory factors. In addition, the expression of some ARSs is dynamically changed depending on various cellular types and stresses. This Analysis article addresses the potential pathophysiological implications of ARSs in tumorigenesis.
Population-based studies have established that long-term intake of non-steroidal anti-inflammatory drugs (NSAIDs), compounds that inhibit the enzymatic activity of cyclooxygenase (COX), reduces the relative risk for developing colorectal cancer. These studies led to the identification of a molecular target, COX-2, that is involved in tumour promotion during colorectal cancer progression. Recent studies in humans indicate that therapy with specific COX-2 inhibitors might be an effective approach to colorectal cancer prevention and treatment.
Advances in genomics, proteomics and molecular pathology have generated many candidate biomarkers with potential clinical value. Their use for cancer staging and personalization of therapy at the time of diagnosis could improve patient care. However, translation from bench to bedside outside of the research setting has proved more difficult than might have been expected. Understanding how and when biomarkers can be integrated into clinical care is crucial if we want to translate the promise into reality.
The RAS proteins control signalling pathways that are key regulators of several aspects of normal cell growth and malignant transformation. They are aberrant in most human tumours due to activating mutations in the RAS genes themselves or to alterations in upstream or downstream signalling components. Rational therapies that target the RAS pathways might inhibit tumour growth, survival and spread. Several of these new therapeutic agents are showing promise in the clinic and many more are being developed.
The physiology of microvessels limits the growth and development of tumours. Tumours gain nutrients and excrete waste through growth-associated microvessels. New anticancer therapies target this microvasculature by inhibiting vascular endothelial growth factor A (VEGF-A) splice isoforms that promote microvessel growth. However, certain VEGF-A splice isoforms in normal tissues inhibit growth of microvessels. Thus, it is the VEGF-A isoform balance, which is controlled by mRNA splicing, that orchestrates angiogenesis. Here, we highlight the functional differences between the pro-angiogenic and the anti-angiogenic VEGF-A isoform families and the potential to harness the synthetic capacity of cancer cells to produce factors that inhibit, rather than aid, cancer growth.
Germline mutation in either BRCA1 or BRCA2 is associated with an increased risk of ovarian cancer, particularly the most common invasive histotype - serous carcinoma. In addition, serous ovarian cancers have an unusually high frequency of other molecular events involving BRCA pathway dysfunction. Recent findings show a high frequency of TP53 mutation, chromosomal instability, distinct molecular subtypes and DNA copy number-driven changes in gene expression. These findings suggest a model in which homologous recombination repair deficiency initiates a cascade of molecular events that sculpt the evolution of high-grade serous ovarian cancer and dictate its response to therapy.
DNA, mRNA and microRNA are released and circulate in the blood of cancer patients. Changes in the levels of circulating nucleic acids have been associated with tumour burden and malignant progression. In the past decade a wealth of information indicating the potential use of circulating nucleic acids for cancer screening, prognosis and monitoring of the efficacy of anticancer therapies has emerged. In this Review, we discuss these findings with a specific focus on the clinical utility of cell-free nucleic acids as blood biomarkers.
Over the past few years, several genes, proteins and signalling pathways that are required for embryogenesis have been shown to regulate tumour development and progression by playing a major part in overriding antitumour safeguard mechanisms. These include axon guidance cues, such as Netrins and Slits. Netrin 1 and members of the Slit family are secreted extracellular matrix proteins that bind to deleted in colorectal cancer (DCC) and UNC5 receptors, and roundabout receptors (Robos), respectively. Their expression is deregulated in a large proportion of human cancers, suggesting that they could be tumour suppressor genes or oncogenes. Moreover, recent data suggest that these ligand-receptor pairs could be promising targets for personalized anticancer therapies.
By eliciting distinct transcriptional responses, the oestrogen receptors (ERs) ERα and ERβ exert opposite effects on cellular processes that include proliferation, apoptosis and migration and that differentially influence the development and the progression of cancer. Perturbation of ER subtype-specific expression has been detected in various types of cancer, and the differences in the expression of ERs are correlated with the clinical outcome. The changes in the bioavailability of ERs in tumours, together with their specific biological functions, promote the selective restoration of their activity as one of the major therapeutic approaches for hormone-dependent cancers.
Experimental evidence suggests that platelets contribute to metastasis through adhesive and haemostatic functions that promote cancer cell survival, immune evasion and interactions with vascular cells to assist organ colonization from the bloodstream. Extensive experimental evidence shows that platelets support tumour metastasis. The activation of platelets and the coagulation system have a crucial role in the progression of cancer. Within the circulatory system, platelets guard tumour cells from immune elimination and promote their arrest at the endothelium, supporting the establishment of secondary lesions. These contributions of platelets to tumour cell survival and spread suggest platelets as a new avenue for therapy.