The aim of this paper is to assess the relevance of somatic evolution by natural selection to our understanding of cancer development. I do so in two steps. In the first part of the paper, I ask to what extent cancer cells meet the formal requirements for evolution by natural selection, relying on Godfrey-Smith’s (2009) framework of Darwinian populations. I argue that although they meet the minimal requirements for natural selection, cancer cells are not paradigmatic (...) Darwinian populations. In the second part of the paper, I examine the most important examples of adaptation in cancer cells. I argue that they are not significant accumulations of evolutionary changes, and that as a consequence natural selection plays a lesser role in their explanation. Their explanation, I argue, is best sought in the previously existing wiring of the healthy cells. (shrink)

Similar to parasites, cancer cells depend on their hosts for sustenance, proliferation and reproduction, exploiting the hosts for energy and resources, and thereby impairing their health and fitness. Because of this lifestyle similarity, it is predicted that cancer cells could, like numerous parasitic organisms, evolve the capacity to manipulate the phenotype of their hosts to increase their own fitness. We claim that the extent of this phenomenon and its therapeutic implications are, however, underappreciated. Here, we review (...) and discuss what can be regarded as cases of host manipulation in the context of cancer development and progression. We elaborate on how acknowledging the applicability of these principles can offer novel therapeutic and preventive strategies. The manipulation of host phenotype by cancer cells is one more reason to adopt a Darwinian approach in cancer research. -/- . (shrink)

It is not clear why cancer cells choose to disrupt their circadian clock rhythms, and whether such disruption governs a selective fitness and a survival advantage. In this review, I focus on understanding the impacts of clock gene disruption on a simpler model, such as the unicellular cyanobacterium, in order to explain how cancer cells may alter the circadian rhythm to reprogram their metabolism based on their needs and status. It appears to be that the activation (...) of the oxidative pentose phosphate pathway (OPPP) and production of NADPH, the preferred molecule for detoxification of reactive oxygen species, is a critical process for night survival in unicellular organisms. The circadian clock acts as a gatekeeper that controls how the organism will utilize its sugar, shifting sugar influx between glycolysis and OPPP. The circadian clock can thus act as a gatekeeper between an anabolic, proliferative mode and a homeostatic, survival mode. (shrink)

Graphical AbstractTo metastasize, cancer cells must be able to complete cell division in environments very different from their tissue of origin. We suggest that mitotic cell rounding, aided by several actin-regulatory oncogenes, may facilitate this process in a robust, context-independent manner.

In recent years the argument has been made that malignant tumors represent complex dynamic and self‐organizing biosystems. Furthermore, there is increasing evidence that collective cell migration is common during invasion and metastasis of malignant tumors. Here, we argue that cancer systems may be capable of developing multicellular collective patterns that resemble evolved adaptive behavior known from other biological systems including collective sensing of environmental conditions and collective decision‐making. We present a concept as to how these properties could arise in (...) tumors and why the emergence of such swarm‐like patterns would confer advantageous properties to the spatiotemporal expansion of tumors, and consequently, why understanding and ultimately targeting such collectivity should be of interest for basic and clinical cancer research alike. (shrink)

Metastatic spread of tumor cells is one of the most common causes of death in cancer patients. Therefore, elucidation of the molecular mechanisms that underlie the formation of metastatic colonies has been one of the major objectives of cancer research during the last two decades. In this review we will mainly discuss the mechanisms that cause a malignant cell to grow at a given site rather than at other possible sites, taking into account experimental and clinical evidence (...) published on the subject. As a whole this evidence tends to confirm the hypothesis that organ‐specific colonization by malignant cells often follows very specific and close interactions between the cancer cell and the target organ, either in terms of specific cellular adhesion or growth promotion. In this paper we would like to underscore the fact that cellular adhesion, either specific or unspecific, is a necessary but, by itself, insufficient condition for the development of metastases. It is the ability of the tumor cells to grow at the site where they arrested that ultimately determines whether a metastatic colony develops or fails to develop at that site. (shrink)

Here I present and discuss a model that, among other things, appears able to describe the dynamics of cancer cell origin from the perspective of stable and unstable gene expression profiles. In identifying suchaberrantgene expression profiles as lying outside the normal stable states attracted through development and normal cell differentiation, the hypothesis explains why cancer cells accumulate mutations, to which they are not robust, and why these mutations create a new stable state far from the normal gene (...) expression profile space. Such cells are in strong contrast with normal cell types that appeared as an attractor state in the gene expression dynamical system under cell‐cell interaction and achieved robustness to noise through evolution, which in turn also conferred robustness to mutation. In complex gene regulation networks, otheraberrantcellular states lacking such high robustness are expected to remain, which would correspond to cancer cells. (shrink)

Cancers often express hundreds of genes otherwise specific to germ cells, the germline/cancer (GC) genes. Here, we present and discuss the hypothesis that activation of a “germline program” promotes cancer cell malignancy. We do so by proposing four hallmark processes of the germline: meiosis, epigenetic plasticity, migration, and metabolic plasticity. Together, these hallmarks enable replicative immortality of germ cells as well as cancer cells. Especially meiotic genes are frequently expressed in cancer, implying that (...) genes unique to meiosis may play a role in oncogenesis. Because GC genes are not expressed in healthy somatic tissues, they form an appealing source of specific treatment targets with limited side effects besides infertility. Although it is still unclear why germ cell specific genes are so abundantly expressed in cancer, from our hypothesis it follows that the germline's reproductive program is intrinsic to cancer development. (shrink)

Cancer is a singular cellular state, the emergence of which destabilises the homeostasis reached through the evolution to multicellularity. We present the idea that the onset of the cellular disobedience to the metazoan functional and structural architecture, known as the cancer phenotype, is triggered by changes in the cell's external environment that occur with ageing: what ensues is a breach of the social contract of multicellular life characteristic of metazoans. By integrating old ideas with new evidence, we propose (...) that with ageing the environmental information that maintains a multicellular organisation is eroded, rewiring internal processes of the cell, and resulting in an internal shift towards an ancestral condition resulting in the pseudo‐multicellular cancer phenotype. Once that phenotype emerges, a new local social contract is built, different from the homeostatic one, leading to tumour formation and the foundation of a novel local ecosystem. (shrink)

Stochastic gene expression plays a leading developmental role through its contribution to cell differentiation. It is also proposed to promote phenotypic diversification in malignant cells. However, it remains unclear if these two forms of cellular bet‐hedging are identical or rather display distinct features. Here we argue that bet‐hedging phenomena in cancer cells are more similar to those occurring in unicellular organisms than to those of normal metazoan cells. We further propose that the atavistic bet‐hedging strategies in (...) cancer originate from a hijacking of the normal developmental bet‐hedging of metazoans. Finally, we discuss the constraints that may shape the atavistic bet‐hedging strategies of cancer cells. (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.

A new therapeutic strategy could break the stalemate in the war on cancer by targeting not all cancerous cells but the small fraction that lie at the root of cancers. Lucie Laplane offers a comprehensive analysis of cancer stem cell theory, based on an original interdisciplinary approach that combines biology, biomedical history, and philosophy.

Cancer viewed as a programmed, evolutionarily conserved life‐form, rather than just a random series of disease‐causing mutations, answers the rarely asked question of what the cancer cell is for, provides meaning for its otherwise mysterious suite of attributes, and encourages a different type of thinking about treatment. The broad but consistent spectrum of traits, well‐recognized in all aggressive cancers, group naturally into three categories: taxonomy (“phylogenation”), atavism (“re‐primitivization”) and robustness (“adaptive resilience”). The parsimonious explanation is not convergent evolution, (...) but the release of an highly conserved survival program, honed by the exigencies of the Pre‐Cambrian, to which the cancer cell seems better adapted; and which is recreated within, and at great cost to, its host. Central to this program is the Warburg Effect, whose malign influence permeates well beyond aerobic glycolysis to include biomass interconversion and genomic heuristics. Warburg‐type metabolism and genomic instability are targets whose therapeutic disablement is a major priority. (shrink)

© Copyright 2015, Mary Ann Liebert, Inc..Signal transducer and activator of transcription factor 3 is hyperactivated in head and neck squamous cell carcinomas. Cumulative evidence indicates that IL-6 production by HNSCC cells and/or stromal cells in the tumor microenvironment activates STAT3 and contributes to tumor progression and drug resistance. A library of 94,491 compounds from the Molecular Library Screening Center Network was screened for the ability to inhibit interleukin-6 -induced pSTAT3 activation. For contractual reasons, the primary high-content screening (...) campaign was conducted over several months in 3 distinct phases; 1,068 primary HCS actives remained after cytotoxic or fluorescent outliers were eliminated. One thousand one hundred eighty-seven compounds were cherry-picked for confirmation; actives identified in the primary HCS and compounds selected by a structural similarity search of the remaining MLSCN library using hits identified in phases I and II of the screen. Actives were confirmed in pSTAT3 IC50 assays, and an IFNγ-induced pSTAT1 activation assay was used to prioritize selective inhibitors of STAT3 activation that would not inhibit STAT1 tumor suppressor functions. Two hundred three concentration-dependent inhibitors of IL-6-induced pSTAT3 activation were identified and 89 of these also produced IC50s against IFN-γ-induced pSTAT1 activation. Forty-nine compounds met our hit criteria: they reproducibly inhibited IL-6-induced pSTAT3 activation by ≥70% at 20 μM; their pSTAT3 activation IC50s were ≤25 μM; they were ≥2-fold selective for pSTAT3 inhibition over pSTAT1 inhibition; a cross target query of PubChem indicated that they were not biologically promiscuous; and they were ≥90% pure. Twenty-six chemically tractable hits that passed filters for nuisance compounds and had acceptable drug-like and ADME-Tox properties by computational evaluation were purchased for characterization. The hit structures were distributed among 5 clusters and 8 singletons. Twenty-four compounds inhibited IL-6-induced pSTAT3 activation with IC50s ≤20 μM and 13 were ≥3-fold selective versus inhibition of pSTAT1 activation. Eighteen hits inhibited the growth of HNSCC cell lines with average IC50s ≤ 20 μM. Four chemical series were progressed into lead optimization: the guanidinoquinazolines, the triazolothiadiazines, the amino alcohols, and an oxazole-piperazine singleton. (shrink)

The clonal evolution model and the cancer stem cell model are two independent models of cancers, yet recent data shows intersections between the two models. This article explores the impacts of the CSC model on the CE model. I show that CSC restriction, which depends on CSC frequency in cancer cell populations and on the probability of dedifferentiation of cancer non-stem cells into CSCs, can favor or impede some patterns of evolution and some processes of evolution. (...) Taking CSC restriction into account for the CE model thus has implications for the way in which we understand the patterns and processes of evolution, and can also provide new leads for therapeutic interventions. (shrink)

The human intestines are constantly under the influence of numerous pathological factors: enteropathogenic microorganisms, food antigens, physico‐chemical stress associated with digestion and bacterial metabolism, therefore it must be provided with a system of protection against adverse impact. Recent studies have shown that Paneth cells play a crucial role in maintaining homeostasis of the small intestines. Paneth cells perform many vital functions aimed at maintaining a homeostatic balance between normal microbiota, infectious pathogens and the human body, regulate the qualitative (...) composition and number of intestinal microorganisms, prevent the introduction of potentially pathogenic species, and protect stem cells from damage. Paneth cells take part in adaptive and protective‐inflammatory reactions. Paneth cells maintain dynamic balance between microbial populations, and the macroorganism, preventing the development of intestinal infections and cancer. They play a crucial role in gastrointestinal homeostasis and may be key factors in the etiopathological progression of intestinal diseases. (shrink)

Cancer stem cells (CSC) represent malignant cell subsets in hierarchically organized tumors, which are selectively capable of tumor initiation and self‐renewal and give rise to bulk populations of non‐tumorigenic cancer cell progeny through differentiation. Robust evidence for the existence of prospectively identifiable CSC among cancer bulk populations has been generated using marker‐specific genetic lineage tracking of molecularly defined cancer subpopulations in competitive tumor development models. Moreover, novel mechanisms and relationships have been discovered that link CSC (...) to cancer therapeutic resistance and clinical tumor progression. Importantly, proof‐of‐principle for the potential therapeutic utility of the CSC concept has recently been provided by demonstrating that selective killing of CSC through a prospective molecular marker can inhibit tumor growth. Herein, we review these novel and translationally relevant research developments and discuss potential strategies for CSC‐targeted therapy in the context of resistance mechanisms and molecular pathways preferentially operative in CSC. (shrink)

Recent studies of prostate cancer and other tumor types have revealed significant support, as well as unexpected complexities, for the application of concepts from normal stem cell biology to cancer. In particular, the cell of origin and cancer stem cell models have been proposed to explain the heterogeneity of tumors during the initiation, propagation, and evolution of cancer. Thus, a basis of intertumor heterogeneity has emerged from studies investigating whether stem cells and/or non‐stem cells (...) can serve as cells of origin for cancer and give rise to tumor subtypes that vary in disease outcome. Furthermore, analyses of putative cancer stem cells have revealed the genetically diverse nature of cancers and expanded our understanding of intratumor heterogeneity and clonal evolution. Overall, the principles that have emerged from these stem cell studies highlight the challenges to be surmounted to develop effective treatment strategies for cancer. (shrink)

The characterisation of normal stem cells and cancer stem cells uses the same paradigm. These cells are isolated by a fluorescence‐activated cell sorting step and their stemness is assayed following implantation into animals. However, differences exist between these two kinds of stem cells. Therefore, the translation of the experimental procedures used for normal stem cell isolation into the research field of cancer stem cells is a potential source of artefacts. In addition, normal stem (...) cell therapy has the objective of regenerating a tissue, while cancer stem cell‐centred therapy seeks the destruction of the cancer tissue. Taking these differences into account is critical for anticipating problems that might arise in cancer stem cell‐centred therapy and for upgrading the cancer stem cell paradigm accordingly. (shrink)

The expression of epithelial cell adhesion and cytoskeletal genes is orchestrated by an apparently unique set of rules. No tissue‐specific transactivator proteins have been found to drive them; only ubiquitous factors are utilized. In non‐epithelial cells, they are actively repressed. Moreover, it was recently found that a single protein (adenovirus E1a) coordinately represses non‐epithelial genes while inducing epithelial genes. A simple model is offered to explain how epithelial gene expression is coordinated. Under this model, the epithelial cell gene expression (...) program is a transcriptional ‘default’; that is, it occurs in the absence of tissue‐specific transactivation. Conversion to this default requires only that mesenchymal transactivators are not expressed, or that central ‘integrator’ proteins are inactive. In their absence, mesenchymal gene expression cannot occur. Moreover, because the repressors cease to be expressed, the epithelial genes are induced. Oncogenes generally cause the breakdown of the epithelial phenotype ‐ generating carcinomas ‐ so genes such as E1a that cause epithelial conversion may prove useful for both understanding and controlling cancer. (shrink)

In spite of the advances in our knowledge of cancer biology, most cancers remain not curable with present therapies. Current treatments consider cancer as resulting from uncontrolled proliferation and are non‐specific. Although they can reduce tumour burden, relapse occurs in most cases. This was long attributed to incomplete tumour elimination, but recent developments indicate that different types of cells contribute to the tumour structure, and that the tumour's cellular organization would be analogous to that of a normal (...) tissue, with a main mass of differentiating cells sensitive to anti proliferative agents, together with a small percentage of quiescent, resistant stem cells responsible for replenishing the tumour: the Cancer Stem Cells (CSCs). Anti‐CSCs targeted therapeutic agents would prevent tumour regeneration. New mouse models tailored to exploit this novel concept will be critical to develop CSC‐based anti‐cancer therapies. Here we review the biological basis and the therapeutic implications of the stem‐cell model of cancer. BioEssays 29:1269–1280, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

What is now familiarly referred to as the ‘embryonic stem (ES) cell’ is a recent biological category whose origins lie in research into benign and malignant teratomas carried out in the 1950s, 60s and 70s. In these studies, the question of the normal or pathological character of the ES cell was a matter of considerable debate and indeed the term ES cell was often used interchangeably with that of the embryonal carcinoma (EC) cell. This article argues that the indecisiveness of (...) the entity known as the ES cell—its refusal to commit to established demarcations between the normal and the pathological—continues to haunt the field of stem cell science. Exploring the prehistory of research into ES cells, early theories of cancer (in particular the embryonal theory expounded by Julius Cohnheim) and recent theoretical critiques of the somatic mutation theory, the article not only points to a shift in understandings of the normal and the pathological but asks under what conditions such shifts are able to take place. (shrink)

Tumors are often viewed as unique entities with specific behaviors. However, tumors are a mixture of differentially evolved subpopulations of cells in constant Darwinian evolution, selecting the fittest clone and allowing it to outgrow the rest. As in the natural environment, the niche defines the properties the fittest clones must possess. Therefore, there can be multiple fit clones because of the various microenvironments inside a single tumor. Hypoxia is considered to be a major feature of the tumor microenvironment and (...) is a potential contributor to the cancer stem cell (CSC) phenotype and its enhanced tumorigenicity. The acidic microenvironment around hypoxic cells is accompanied by the activation of a subset of proteases that contribute to metastasis. Because of aberrant angiogenesis and the inaccessibility of their locations, hypoxic cells are less likely to accumulate therapeutic concentrations of chemotherapeutics that can lead to therapeutic resistance. Therefore, the targeting of the hypoxic CSC niche in combination with chemotherapy may provide a promising strategy for eradicating CSCs. In this review, we examine the cancer stem cell hypothesis and its relationship to the microenvironment, specifically to hypoxia and the subsequent metabolic switch and how they shape tumor behavior. (shrink)

Inflamm‐aging is a relatively new terminology used to describe the age‐related increase in the systemic pro‐inflammatory status of humans. Here, we represent inflamm‐aging as a breakdown in the multi‐shell cytokine network, in which stem cells and stromal fibroblasts (referred to as the stem cell niche) become pro‐inflammatory cytokine over‐expressing cells due to the accumulation of DNA damage. Inflamm‐aging self‐propagates owing to the capability of pro‐inflammatory cytokines to ignite the DNA‐damage response in other cells surrounding DNA‐damaged cells. (...) Macrophages, the major cellular player in inflamm‐aging, amplify the phenomenon, by broadcasting pro‐inflammatory signals at both local and systemic levels. On the basis of this, we propose that inflamm‐aging is a major contributor to the increase in cancer incidence and progression in aged people. Breast cancer will be presented as a paradigmatic example for this relationship. (shrink)

Recently, Quyn et al. demonstrated that cells within the stem cell zone of human and mouse intestinal crypts tend to align their mitotic spindles perpendicular to the basal membrane of the crypt. This is associated with asymmetric division, whereby particular proteins and individual chromatids are preferentially segregated to one daughter cell. In colonic mucosa containing a heterozygous adenomatous polyposis coli gene (APC) mutation the asymmetry is lost. Here, we discuss asymmetric stem cell division as an anti‐tumourigenic mechanism. We describe (...) how hierarchical tissue structures suppress somatic evolution, and discuss the relative merits of template strand retention to limit the accumulation of DNA replication errors. We suggest experiments to determine whether somatic mutations resulting in loss of spindle alignment confer an advantage within the stem cell niche. Finally, we discuss whether lack of spindle alignment constitutes an oncogenic event per se, with particular reference to studies in model organisms, and the timing of chromosomal instability in human cancers. (shrink)

This book explores a variety of conceptual and methodological questions about cancer and cancer research: Is cancer one disease, or many? If many, how many exactly? How is cancer classified? What does it mean, exactly, to say that cancer is “genetic,” or “familial”? What exactly are the causes of cancer, and how do scientists come to know about them? When do we have good reason to believe that this or that is a risk factor (...) for cancer? How is cancer a product or byproduct of multilevel evolution? Is cancer research unified? What sort of models, or theories, govern cancer research? This book takes a close look at these philosophical questions, by examining work in disciplines as diverse as cell and molecular biology, epidemiology, clinical medicine, and evolutionary biology. (shrink)

In the atavistic model of cancer progression, tumor cell dedifferentiation is interpreted as a reversion to phylogenetically earlier capabilities. The more recently evolved capabilities are compromised first during cancer progression. This suggests a therapeutic strategy for targeting cancer: design challenges to cancer that can only be met by the recently evolved capabilities no longer functional in cancer cells. We describe several examples of this target‐the‐weakness strategy. Our most detailed example involves the immune system. The (...) absence of adaptive immunity in immunosuppressed tumor environments is an irreversible weakness of cancer that can be exploited by creating a challenge that only the presence of adaptive immunity can meet. This leaves tumor cells more vulnerable than healthy tissue to pathogenic attack. Such a target‐the‐weakness therapeutic strategy has broad applications, and contrasts with current therapies that target the main strength of cancer: cell proliferation. (shrink)

Dlg (Discs large), Scrib (Scribble) and Lgl (Lethal giant larvae) are evolutionarily conserved components of a common genetic pathway that link the seemingly disparate functions of cell polarity and cell proliferation in epithelial cells. dlg, scrib and lgl have been identified as tumour suppressor genes in Drosophila, mutations of which cause similar phenotypes, involving disruption of cell polarity and neoplastic overgrowth of tissues. The molecular mechanisms by which Dlg, Scrib and Lgl proteins regulate cell proliferation are not clear, but (...) there is some evidence that epithelial polarisation is required for this regulation. Dlg, Scrib and Lgl are highly conserved between human and Drosophila, and we discuss evidence that these proteins also play a role in cancer progression in humans. BioEssays 25:542–553, 2003. © 2003 Wiley Periodicals, Inc. (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)

Silencing of tumor suppressor genes (TSGs), by DNA methylation, is well known in adult cancers. However, based on the “stem cell” theory of tumorigenesis, the early epigenetic events arising in malignant precursors remain unknown. A recent report1 demonstrates that, while pluripotent embryonic stem cells lack DNA methylation and possess a “bivalent” pattern of activating and repressive histone marks in numerous TSGs, analogous multipotent malignant cells derived from germ cell tumors (embryonic carcinoma cells) gain additional silencing modifications to (...) those same genes. These results suggest a possible mechanism by which aberrant differentiation, mediated by histone and DNA methylation, instigates tumor progression. BioEssays 29:842–845, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

An effectiveness assessment on ASCT in locally advanced and metastatic breast cancer identified serious ethical issues associated with this intervention. Our objective was to systematically review these aspects by means of a literature analysis. We chose the reflexive Socratic approach as the review method using Hofmann's question list, conducted a comprehensive literature search in biomedical, psychological and ethics bibliographic databases and screened the resulting hits in a 2-step selection process. Relevant arguments were assembled from the included articles, and were (...) assessed and assigned to the question list. Hofmann's questions were addressed by synthesizing these arguments. Of the identified 879 documents 102 included arguments related to one or more questions from Hofmann's question list. The most important ethical issues were the implementation of ASCT in clinical practice on the basis of phase-II trials in the 1990s and the publication of falsified data in the first randomized controlled trials (Bezwoda fraud), which caused significant negative effects on recruiting patients for further clinical trials and the doctor-patient relationship. Recent meta-analyses report a marginal effect in prolonging disease-free survival, accompanied by severe harms, including death. ASCT in breast cancer remains a stigmatized technology. Reported health-related-quality-of-life data are often at high risk of bias in favor of the survivors. Furthermore little attention has been paid to those patients who were dying. The questions were addressed in different degrees of completeness. All arguments were assignable to the questions. The central ethical dimensions of ASCT could be discussed by reviewing the published literature. (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)

Major problems in cancer chemotherapy are toxicity, resistance, and cancer heterogeneity. A new theranostic paradigm has been proposed by the authors. Many million small molecules (SM) are bound to the proteins extracted from a patient's cancer. SM that also bind proteins extracted from normal human tissues are subtracted from the cancer protein bound SM leaving a large array of SM targeting many sites on each of the cancer biomarkers. Targeting many more than the conventional 1 (...) – 4 cancer biomarkers will reduce development of tumor resistance. After several cycles of selection and counter selection, DNA codes appended to the SM will be PCR amplified to provide templates for restricted libraries of the SM to improve selectivity and sensitivity. The large array of selected and counter selected SM assures that many of the compounds in the array will penetrate the cell membrane and bind to intracellular targets, low tumor resistance, low background for imaging, low therapeutic toxicity, and targeting of the diverse biomarkers present in the heterogeneous mixture of cells in primary and metastatic cancer. Theranostic use of radiolabeled SM binding many sites on many, not necessarily critical, biomarkers provides high cancer cell killing. Experiments to provide proof of principle of this novel concept suggested by the authors. -/- . (shrink)

This article provides a historical, philosophical, and psychological analysis of the recent discovery that reoviruses are oncolytic, capable of infecting and destroying many kinds of cancer cells. After describing Patrick Lee's very indirect path to this discovery, I discuss the implications of this case for understanding the nature of scientific discovery, including the economy of research, anomaly recognition, hypothesis formation, and the role of emotion in scientific thinking. Lee's discoveries involved a combination of serendipity, abductive and deductive inference, (...) and emotional cognition. (shrink)

Cancer is a paradigmatic case of a complex causal process; causes of cancer operate at a variety of temporal and spatial scales, and the respects in which these causes act and interact are diverse. There are, for instance, temporal order effects, organizational effects, structural effects, and dynamic relationships between causes operating at different temporal and spatial scales. Because of this complexity, models of cancer initiation and progression often involve deliberate choices to focus on one time scale, one (...) causal pathway, or one aspect of cancer’s dynamics. As in most of biology, modeling cancer involves simplification and idealization. At the same time, theoretical perspectives inform the construction of these models. Such perspectives might involve viewing cancer ‘as’ a genetic disease, metabolic disease, stem cell disease, an infectious disease, or a disease of tissue disorganization. This paper will argue that purportedly competing theoretical views of cancer are not at odds, but can be viewed as mutually informative. Models are most often developed in the service of asking very specific questions, and this requires limiting our view of the phenomena to a specific temporal or spatial scale, a particular cause, or a particular outcome, dynamic, or pattern. Thus, while some models may seem at odds, often they are simply concerned with different questions, or, they are complementary and mutually informative. I hope to bring this case to bear on debates among philosophers of science over perspectivism and realism, as well pluralism about the aims and scope of scientific theory. (shrink)

During tumor evolution, cancer cells use the tumor‐stroma crosstalk to reorganize the microenvironment for maximum robustness of the tumor. The success of immune checkpoint therapy foretells a new cancer therapy paradigm: an effective cancer treatment should not aim to influence the individual components of super complex intracellular interactomes (molecular targeting), but try to disrupt the intercellular interactions between cancer and stromal cells, thus breaking the tumor as a whole. Arguments are provided in favor of (...) a hypothesis that such interactions include formation of synapse‐like structures (interfaces) where the interacting cells are located at a distance of ∼10–15 nm. Within these interfaces, molecules initiating and strengthening the interaction are organized, and allow optimum cross‐signaling; a very confined intercellular space facilitates the concentration of secreted cytokines, enhancing the paracrine cross‐communication. These features of tumors form a druggable cancer hallmark the tumor‐stroma symbiotic crosstalk—which represents a new target for efficient cancer drug discovery. (shrink)

Transmissible cancers are elusive and understudied parasitic life forms caused by malignant clonal cells (nine lineages are known so far). They emerge by completing sequential steps that include breaking cell cooperation, evade anti‐cancer defences and shedding cells to infect new hosts. Transmissible cancers impair host fitness, and their importance as selective force is likely largely underestimated. It is, therefore, crucial to determine how common they might be in the wild. Here, we draw a parallel between the steps (...) required for a transmissible cancer to emerge and the steps required for an intelligent civilisation to emerge in the Milky Way using a modified Drake equation. Using numerical analyses, we estimate the potential number of extant marine and bivalve species in which transmissible cancers might exist. Our results suggest that transmissible cancers are more common than expected, and that new lineages can be found by screening a large number of species. (shrink)

Cancer cells seem to exploit mechanisms that evolve as part of physiological tolerance, which is a complementary and often beneficial form of defense. The study of physiological systems of tolerance can therefore provide insights into the development of a state of host tolerance of cancer, and how to break it. Analysis of these models has the potential to improve our understanding of existing immunological therapeutic targets, and help to identify future targets and rational therapeutic combinations. The treatment (...) of cancer with immune checkpoint inhibitors aims to reverse the progression to tolerance of cancer, and achieve an immunogenic, rather than tolerogenic, homeostasis. Broadening the efficacy and durability of checkpoint inhibitors focuses on reversing tolerance and stimulating immunogenicity in the cancer, host, and environment. Two examples of important physiological states of tolerance that may inform tolerance of cancer are microbial infection and placental reproduction. These states of tolerance result from bilateral shaping of host and non‐self, akin to immunoediting in cancer, and offer reliable models to study the immune tolerance paradigm. (shrink)