The human tumour suppressor protein p53 is critical for regulation of the cell cycle on genotoxic insult. When DNA is damaged by radiation, chemicals or viral infection, cells respond rapidly by arresting the cell cycle. A G1 arrest requires the activity of wild‐type p53, as it is not observed in cells lacking functionally wild‐type protein, and at least some component of S phase and G2/M arrests is also thought to be p53‐dependent. p53 functions as a transcription factor which binds specific (...) DNA sequences, and recently major downstream targets have been identified, including p21Cip1 an inhibitor of the cell cycle kinases that also blocks the replicative but not the repair function of DNA polymerase δ auxiliary factor, PCNA. Current interest focuses on developing novel cancer therapies based on our knowledge of the activity of p53 and p21Cip1 in the cell cycle. (shrink)

Molecular tumour boards (MTBs) offer recommendations for potentially effective, but potentially burdensome, molecularly targeted treatments to a patient's treating physician. In this paper, we discuss the question of who is responsible for ensuring that there is an adequate evidence base for any treatments recommended to a patient. We argue that, given that treating oncologists cannot usually offer a robust evaluation of the evidence underlying an MTB's recommendation, members of the MTB are responsible for ensuring that the evidence level is adequate. (...) We explore two models for how to share responsibility between MTB members. According to the first model, each MTB member, as well as the treating physician, should be held maximally and equally responsible for the recommendations. We argue that this insufficiently accounts for differences in roles and expertise of MTB members. We propose instead that responsibility is delegated via relationships of trust. We argue if these relationships of trust are to be instances of reasonable trust, (a) MTBs should offer a clinical representative to whom a treating physician may delegate the responsibility of ensuring there is sufficient evidence for treatment recommendations, (b) the relationships of trust between the representative and the other MTB members should be clearly defined, and (c) MTB members should be carefully selected. Treating oncologists retain a responsibility to consider general limitations of the evidence for targeted treatments in assessing whether the treatment recommendation offered by an MTB's representative is adequate for a given clinical situation. (shrink)

Over the last few years, oncolytic virus therapy has been recognised as a promising approach in cancer treatment, due to the potential of these viruses to induce systemic anti-tumour immunity and selectively killing tumour cells. However, the effectiveness of these viruses depends significantly on their interactions with the host immune responses, both innate and adaptive. In this article, we consider a mathematical approach to investigate the possible outcomes of the complex interactions between two extreme types of macrophages, effector $$\hbox {CD8}^{+}$$ (...) T cells and an oncolytic Vesicular Stomatitis Virus, on the growth/elimination of B16F10 melanoma. We discuss, in terms of VSV, $$\hbox {CD8}^{+}$$ and macrophages levels, two different types of immune responses which could ensure tumour control and eventual elimination. We show that both innate and adaptive anti-tumour immune responses, as well as the oncolytic virus, could be very important in delaying tumour relapse and eventually eliminating the tumour. Overall this study supports the use mathematical modelling to increase our understanding of the complex immune interaction following oncolytic virotherapies. However, the complexity of the model combined with a lack of sufficient data for model parametrisation has an impact on the possibility of making quantitative predictions. (shrink)

In normal human cells, a protein with a molecular weight of about 53,000 (p53) is present at a low level, detectable only by sensitive assays. When the cells are infected with some DNA tumour viruses or transformed by the same viruses, the amount of this protein increases dramatically, and much of it is found in a physical association with the virus‐coded protein that causes the transformation. The increase in amount and, incidentally, stability of p53 is not peculiar to virus‐transformed cells, (...) but also occurs in cells transformed by chemicals or radiation where there is no sign of any virus being involved (reviewed by Crawford).1 Cells in culture are not the same as cells in a patient, but these observations do raise questions about the possible involvement of p53 in human tumours. (shrink)

In response to DNA‐damage, cells have to decide between different cell fate programmes. Activation of the tumour suppressor HIPK2 specifies the DNA damage response (DDR) and tips the cell fate balance towards an apoptotic response. HIPK2 is activated by the checkpoint kinase ATM, and triggers apoptosis through regulatory phosphorylation of a set of cellular key molecules including the tumour suppressor p53 and the anti‐apoptotic corepressor CtBP. Recent work has identified HIPK2 as a regulator of the ultimate step in cytokinesis: the (...) abscission of the mother and daughter cells. Since proper cytokinesis is essential for genome stability and maintenance of correct ploidy, this finding sheds new light on the tumour suppressor function of HIPK2. Here we highlight the molecular mechanisms coordinating HIPK2 function and discuss its emerging role as a tumour suppressor. (shrink)

In order to accomplish the transition from avascular to vascular growth, solid tumours secrete a diffusible substance known as tumour angiogenesis factor (TAF) into the surrounding tissue. Endothelial cells which form the lining of neighbouring blood vessels respond to this chemotactic stimulus in a well-ordered sequence of events comprising, at minimum, of a degradation of their basement membrane, migration and proliferation. Capillary sprouts are formed which migrate towards the tumour eventually penetrating it and permitting vascular growth to take place. (...) It is during this stage of growth that the insidious process of invasion of surrounding tissues can and does take place. A model mechanism for angiogenesis is presented which includes the diffusion of the TAF into the surrounding host tissue and the response of the endothelial cells to the chemotactic stimulus. Numerical simulations of the model are shown to compare very well with experimental observations. The subsequent vascular growth of the tumour is discussed with regard to a classical reaction-diffusion pre-pattern model. (shrink)

From the viewpoint of an evolutionary biologist, carcinogenesis should be looked upon as a protective mechanism against destruction of DNA. Because genes expressed in embryonic cells are covered and protected by heterochromatinization, they are the most appropriate ‘alternate genes’ compared to genes that are expressed already in somatic cells. When DNA-damage occurs, the embryonic genes can be activated. Some somatic cells exhibit some features of embryonic cells.

This brief report raises the ethical dilemma encountered by an obstetrician involved in the care of a pregnant woman with life-threatening disease. This is a particularly difficult issue if the maternal well-being is in conflict with the survival of the unborn child.

Background:Caring for a partner with primary malignant brain tumour can be a dramatic life-changing event. Primary malignant brain tumour is known to give poor life expectancy and severe neurological and cognitive symptoms, such as changed behaviour and personality, which demand greater caring responsibilities from spouses.Aim:The aim of the study is to explore ethical dilemmas spouses experience in the everyday care of a partner in treatment for primary malignant brain tumour.Research design, participants and research context:A phenomenological and hermeneutic qualitative descriptive design (...) was adopted as a method for collecting and analysing data. Ten spouses were interviewed twice using an in-depth, semi-structured interview guide. The interviews took place at the spouses’ homes or at the hospital.Ethical consideration:Ethical matters were considered throughout the research process. Permission from The National Committee on Health Research Ethics and the Danish Data Protection Agency was obtained.Findings:The analysis showed that the spouses perceived daily ethical dilemmas in caring for a partner with primary malignant brain tumour. Their life as well as their partner’s life had changed considerably. The main theme that emerged therefore was ‘oscillating in a changing relationship’. This theme was further elaborated in three subthemes that in more detail demonstrated the dilemmas: ‘doing the right thing in unpredictable daily situations’; ‘torn between patience and guilt’; and ‘living in a time of uncertainty, hope and despair’.Conclusion:Caring for a partner with changed behaviour and personality due to primary malignant brain tumour may involve exhausting ethical caring dilemmas. Spouses’ married life may change to a semi-professional asymmetrical relationship, which is challenged by the oscillation between acting responsibly for their partners’ well-being and caring dilemmas with no answer for what the right thing to do is. Mixed feelings of right and wrong, patience and guilt, hope and despair seem to be spousal companions through their partners’ progressing illness. (shrink)

This paper discusses the evidence for the role of CREB in neural stem/progenitor cell (NSPC) function and oncogenesis and how these functions may be important for the development and growth of brain tumours. The cyclic‐AMP response element binding (CREB) protein has many roles in neurons, ranging from neuronal survival to higher order brain functions such as memory and drug addiction behaviours. Recent studies have revealed that CREB also has a role in NSPC survival, differentiation and proliferation. Recent work has (...) shown that over‐expression of CREB in transgenic animals can impart oncogenic properties on cells in various tissues and that aberrant CREB expression is associated with tumours in patients. It is the central position of CREB, downstream of key developmental and growth signalling pathways, which give CREB the ability to influence a spectrum of cell activities, such as cell survival, growth and differentiation in both normal and cancer cells. (shrink)

The skin, uniquely positioned at the interface between the human body and the external world, plays a multifaceted immunologic role in human life. In medical practice, early accurate detection of all types of skin tumours is essential to guide appropriate management and improve patients’ survival. The most important issue is to differentiate between malignant skin tumours and benign lesions. The aim of this research is the classification of skin tumours by analysing medical skin tumour dermoscopy images. This (...) paper is focused on a new strategy based on deep convolutional neural networks which have recently shown a state-of-the-art performance to define strategy to automatic classification for skin tumour images. The proposed system is tested on well-known HAM10000 data set. For experimental results, verification is performed and the results are compared with similar researches. (shrink)

A deficit in the number of organs available for transplantation persists even with an increase in donation rates. One possible choice of donor for organs that appears under-referred and/or unaccepted is patients with primary brain tumours. In spite of advances in the treatment of high-grade primary central nervous system (CNS) tumours, the prognosis remains dire. A working group on organs from donors with primary CNS tumours showed that the risk of transmission is small and outweighs the benefits (...) of waiting for a normal donor, in survival and organ life-years, with caveats. This paper explores the possibility that, if information on organ donation were made available to patients and their families with knowledge of their inevitable fate, perhaps some will choose to donate. It would be explained that to achieve this, elective ventilation would be performed in their final moments. This would obviate the consent question because of an advance statement. It is accepted that these are sensitive matters and there will be logistic issues. This will need discussion with the public and other professionals, but it could increase the number of donors and can be extrapolated to encompass other primary CNS tumours. (shrink)

Angiogenesis is central to both the growth and metastasis of solid tumours. Anti‐angiogenic strategies result in blood vessel regression accompanied by tumour cell apoptosis. Radiotherapy and many chemotherapeutic agents kill tumours by inducing apoptotic cell death. We propose that, in addition to its role as an angiogenic factor, vascular endothelial growth factor (VEGF) can act as a survival factor for tumour cells protecting them from apoptosis. Thus anti‐angiogenics, in particular those directed against VEGF, have multiple anti‐tumour effects. We (...) suggest that anti‐VEGF strategies prevent vessel growth and block a tumour cell survival factor, VEGF, rendering tumour cells more sensitive to chemotherapy and radiotherapy. In addition, as chemotherapy and radiotherapy have been shown to increase VEGF expression, anti‐VEGF strategies may overcome therapy‐ induced tumour cell resistance. BioEssays 24:280–283, 2002. © 2002 Wiley Periodicals, Inc.; DOI 10.1002/bies.10043. (shrink)

With a previous paper (Niu & Wang, 1995), a general, hypothetical outline of the mechanism of carcinogenesis was proposed. With reference to the fact of starvation-induced hypermutation in micro-organisms, we propose that the hypoxia commonly seen in the cells at the centre of solid tumours might also result in hypermutation, and then p53-dependent programmed cell death. Like the apparently adaptive mutations in micro-organisms, only those genes (e.g. p53) that enable the cells to escape from apoptosis may be selected.

Mathematical models of tumour invasion appear as interesting tools for connecting the information extracted from medical imaging techniques and the large amount of data collected at the cellular and molecular levels. Most of the recent studies have used stochastic models of cell translocation for the comparison of computer simulations with histological solid tumour sections in order to discriminate and characterise expansive growth and active cell movements during host tissue invasion. This paper describes how a deterministic approach based on reaction-diffusion models (...) and their generalisation in the mechano-chemical framework developed in the study of biological morphogenesis can be an alternative for analysing tumour morphological patterns. We support these considerations by reviewing two studies. In the first example, successful comparison of simulated brain tumour growth with a time sequence of computerised tomography (CT) scans leads to a quantification of the clinical parameters describing the invasion process and the therapy. The second example considers minimal hypotheses relating cell motility and cell traction forces. Using this model, we can simulate the bifurcation from an homogeneous distribution of cells at the tumour surface toward a nonhomogeneous density pattern which could characterise a pre-invasive stage at the tumour-host tissue interface. (shrink)

We examine the consequences of long-range effects on tumour cell migration. Our starting point are previous results of ours where we have shown that the migration patterns of glioma cells are best interpreted if one assumes attractive interactions between cells. Here we complement the cellular automaton model previously introduced by the assumption of the existence of a chemorepellent produced by the main bulk of large spheroids (in the hypoxic/necrotic areas). Visible effects due to the presence of such a substance can (...) be found in the density profiles of cells migrating out of a single spheroid as well as in the angular distribution of cells coming from two close-lying spheroids. These effects depend crucially on the diffusion speed of the chemorepellent. A comparison of the simulation results to experimental data of Werbowetski et al. allows to draw (tentative) conclusions on the existence of a chemorepellent and its properties. (shrink)

Surgical resection of a primary tumour is often not sufficient to cure a patient. Even when no residual cancer can be detected at time of surgery, metastases may appear in the following years, which indicates that the primary tumour had apparently spread before surgery. Following surgery, systemic chemotherapy may be used to eradicate micro‐metastatic disease. Here we present two unconventional strategies that implement new insights into tumour biology and tumour immunology in the treatment of patients with cancer. Both experimental strategies (...) use the individual characteristics of the patient's primary tumour to optimise the control of life‐threatening micro‐metastases. We aim to modulate the patient's adaptive immune system, targeting it towards the patient's own tumour cells to eradicate residual disease following local treatment. In one approach, this is done by autologous tumour cell vaccinations as adjuvant treatment for colon cancer patients and, in a second approach, by giving chemo‐imunotherapy before local treatment to women with locally advanced breast cancer. BioEssays 25:79–86, 2003. © 2002 Wiley Periodicals, Inc. (shrink)

The repertoire of acceptor glycoproteins for concanavalin A expressed by a cultured tumour cell reflects the normal developmental lineage from which it was derived, as well as the degree of maturation along that lineage. Antibodies to this particular set of glycoproteins show a considerable specificity towards normal differentiation antigens which are often preferentially associated with the less mature intermediates of the corresponding pathway. In addition, comparisons between ‘immature’ and ‘mature’ tumour cells can be used to identify glycoproteins associated with specific (...) differentiated functions such as secretion. Thus tumour cell glycoproteins provide useful probes for analysis of the molecular biology of development and differentiation. (shrink)

At the Liverpool Ocular Oncology Centre (LOOC), patients with an eye tumour are offered rapid treatment. Procedures such as enucleation (surgical removal of the eye) are usually performed within 24 hours of initial assessment. Such expedited treatment can be challenged on the basis that it is incompatible with valid consent. We present the results of a questionnaire audit exploring the views of patients on how long they waited to undergo invasive procedures for intraocular melanoma. The findings inform a discussion of (...) three plausible reasons for doubting the validity of consent to rapid intervention: the distress of diagnosis may temporarily undermine patients' capacity to choose; the decision may be too complex to make quickly; and rapid availability of treatment may be unduly influential, undermining the voluntariness of the decision. Using the example of enucleation, we argue that, with adequate safeguards, rapid intervention does not undermine the validity of patients' consent. (shrink)

Clonal studies of adult chimaeric mouse epithelium have demonstrated the monoclonal composition of crypts of Lieberkühn(1). In neonatal life, however, polyclonal crypts have been found, indicating that crypts are of polyclonal origin(2). We here relate these findings to studies of mosaic tissues which have addressed the question whether solid tumours are of monoclonal or polyclonal origin (ref. 3 for review, 4). The issues has so far remained unresolved because the expected frequencies of polyclonal tumours, given polyclonal origins, have (...) not previously been estimated. A general approach for the calculation of such expected values is suggested. The consistent reports of tumours with polyclonal components suggest that autocrine or paracrine mechanisms play an important role during tumorigenesis. (shrink)

Cancers rely on multiple, heterogeneous processes at different scales, pertaining to many biomedical fields. Therefore, understanding cancer is necessarily an interdisciplinary task that requires placing specialised experimental and clinical research into a broader conceptual, theoretical, and methodological framework. Without such a framework, oncology will collect piecemeal results, with scant dialogue between the different scientific communities studying cancer. We argue that one important way forward in service of a more successful dialogue is through greater integration of applied sciences (experimental and clinical) (...) with conceptual and theoretical approaches, informed by philosophical methods. By way of illustration, we explore six central themes: (i) the role of mutations in cancer; (ii) the clonal evolution of cancer cells; (iii) the relationship between cancer and multicellularity; (iv) the tumour microenvironment; (v) the immune system; and (vi) stem cells. In each case, we examine open questions in the scientific literature through a philosophical methodology and show the benefit of such a synergy for the scientific and medical understanding of cancer. (shrink)

Cancer is an evolutionary and ecological process in which complex interactions between tumour cells and their environment share many similarities with organismal evolution. Tumour cells with highest adaptive potential have a selective advantage over less fit cells. Naturally occurring transmissible cancers provide an ideal model system for investigating the evolutionary arms race between cancer cells and their surrounding micro‐environment and macro‐environment. However, the evolutionary landscapes in which contagious cancers reside have not been subjected to comprehensive investigation. Here, we provide a (...) multifocal analysis of transmissible tumour progression and discuss the selection forces that shape it. We demonstrate that transmissible cancers adapt to both their micro‐environment and macro‐environment, and evolutionary theories applied to organisms are also relevant to these unique diseases. The three naturally occurring transmissible cancers, canine transmissible venereal tumour (CTVT) and Tasmanian devil facial tumour disease (DFTD) and the recently discovered clam leukaemia, exhibit different evolutionary phases: (i) CTVT, the oldest naturally occurring cell line is remarkably stable; (ii) DFTD exhibits the signs of stepwise cancer evolution; and (iii) clam leukaemia shows genetic instability. While all three contagious cancers carry the signature of ongoing and fairly recent adaptations to selective forces, CTVT appears to have reached an evolutionary stalemate with its host, while DFTD and the clam leukaemia appear to be still at a more dynamic phase of their evolution. Parallel investigation of contagious cancer genomes and transcriptomes and of their micro‐environment and macro‐environment could shed light on the selective forces shaping tumour development at different time points: during the progressive phase and at the endpoint. A greater understanding of transmissible cancers from an evolutionary ecology perspective will provide novel avenues for the prevention and treatment of both contagious and non‐communicable cancers. (shrink)

Similar to parasites, malignant cells exploit the host for energy, resources and protection, thereby impairing host health and fitness. Although cancer is widespread in the animal kingdom, its impact on life history traits and strategies have rarely been documented. Devil facial tumour disease, a transmissible cancer, afflicting Tasmanian devils, provides an ideal model system to monitor the impact of cancer on host life-history, and to elucidate the evolutionary arms-race between malignant cells and their hosts. Here we provide an overview of (...) parasite-induced host life history adaptations, then both phenotypic plasticity of LH responses and changes in allele frequencies that affect LH traits of Tasmanian devils in response to DFTD are discussed. We conclude that akin to parasites, cancer can directly and indirectly affect devil LH traits and trigger host evolutionary responses. Consequently, it is important to consider oncogenic processes as a selective force in wildlife. Exposure to transmissible cancer cells, i.e., Tasmanian devil facial tumour cells, can cause changes to life history traits either as the result of phenotypic plasticity in response to exposure during the lifetime of the individual or as the result of evolutionary change in LH traits due to selection over generations.Photo credits: Frédéric Thomas, Sarah Peck, Geordie Jennings. (shrink)

Cancer is generally defined as uncontrollable growth of cells caused by genetic aberrations and/or environmental factors. Yet contagious cancers also occur. The recent emergence of a contagious cancer in Tasmanian devils has reignited interest in transmissible cancers. Two naturally occurring transmissible cancers are known: devil facial tumour disease and canine transmissible venereal tumour. Both cancers evolved once and have then been transmitted from one individual to another as clonal cell lines. The dog cancer is ancient; having evolved more than 6,000 (...) years ago, while the devil disease was first seen in 1996. In this review I will compare and contrast the two diseases focusing on the life histories of the clonal cell lines, their evolutionary trajectories and the mechanisms by which they have achieved immune tolerance. A greater understanding of these contagious cancers will provide unique insights into the role of the immune system in shaping tumour evolution and may uncover novel approaches for treating human cancer. (shrink)

The cyclic GMP‐AMP synthase–stimulator of interferon genes (cGAS‐STING) pathway is central for the initiation of anti‐tumoural immune responses. Enormous effort has been made to optimise the design and administration of STING agonists to stimulate tumour immunogenicity. However, in certain contexts the cGAS‐STING axis fuels tumourigenesis. Here, we review recent findings on the regulation of cGAS expression and activity. We particularly focus our attention on the DNA‐dependent protein kinase (DNA‐PK) complex, that recently emerged as an activator of inflammatory responses in tumour (...) cells. We propose that stratification analyses on cGAS and DNA‐PK expression/activation status should be carried out to predict treatment efficacy. We herein also provide insights into non‐canonical functions borne by cGAS and cGAMP, highlighting how they may influence tumourigenesis. All these parameters should be taken into consideration concertedly to choose strategies aiming to effectively boost tumour immunogenicity. (shrink)