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.

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)

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)

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)

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)

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)

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)

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)

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)

This chapter brings a philosophical perspective to the concept of stem cell. Three general questions both clarify the concept of stem cell and emphasize its ambiguities: (1) How should we define stem cells? (2) What makes them different from non-stem cells? (3) What is their ontology? (i.e. what kind of property is “stemness”?) Following this last question, the Chapter distinguishes four conceptions of stem cells and highlights their respective consequences for the (...) class='Hi'>cancer stem cell theory. Determining what kind of property stemness is, in what context, is an urgent question, at least for therapeutic strategies against cancers. I hope that this chapter also illustrates how philosophy can be useful to biology. -/- The Chapter starts by clarifying the notions of self-renewal and differentiation. This leads to the question “can we (and if so, how) distinguish stem cells from non-stem cells through these two properties?”. From that will follow an interrogation on whether stem cells belong to a natural kind. On this issue, biologists and philosophers have framed the following alternative: either the concept of stem cell refers to entities (the cells that belong to the stem cell natural kind) or it refers to a transient and reversible cell state. I will argue that four conceptions of stemness should be distinguished rather than two. Finally, I will develop the case of the cancer stem cell (CSC) theory in order to show why it is crucial to answer the ontological question: some therapies might or might not be efficient depending on what stemness is. (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)

Background: 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. Methods: 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. Results: 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. Conclusions: 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)

Much of the current research in regenerative medicine concentrates on stem-cell therapy that exploits the regenerative capacities of stem cells when injected into different types of human tissues. Although new therapeutic paths have been opened up by induced pluripotent cells and human mesenchymal cells, the rate of success is still low and mainly due to the difficulties of managing cell proliferation and differentiation, giving rise to non-controlled stem cell differentiation that ultimately leads to (...) class='Hi'>cancer. Despite being still far from becoming a reality, these studies highlight the role of physical and biological constraints (e.g., cues and morphogenetic fields) placed by tissue microenvironment on stem cell fate. This asks for a clarification of the coupling of stem cells and microenvironmental factors in regenerative medicine. We argue that extracellular matrix and stem cells have a causal reciprocal and asymmetric relationship in that the 3D organization and composition of the extracellular matrix establish a spatial, temporal, and mechanical control over the fate of stem cells, which enable them to interact and control (as well as be controlled by) the cellular components and soluble factors of microenvironment. Such an account clarifies the notions of stemness and stem cell regeneration consistently with that of microenvironment. (shrink)

In 1998, researchers established the first human embryonic stem cell line. Their scientific triumph triggered an ethics and policy argument that persists today. Bioethicists, religious leaders, government officials, patient advocates, and scientists continue to debate whether this research poses a promise, a threat, or a mixed ethical picture for society.Scientists are understandably excited about the knowledge that could come from studying human embryonic stem cells. Most of them believe these cells offer a precious opportunity to learn (...) more about why diseases develop and how they might be prevented or attacked. In their quest to gain support for stem cell research, scientists and others have claimed that the research could generate cures and treatment for everything from heart disease to cancer. (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)

BackgroundIn 2004, patient advocate groups were major players in helping pass and implement significant public policy and funding initiatives in stem cells and regenerative medicine. In the following years, advocates were also actively engaged in Washington DC, encouraging policy makers to broaden embryonic stem cell research funding, which was ultimately passed after President Barack Obama came into office. Many advocates did this because they were told stem cell research would lead to cures. After waiting more than (...) 10 years, many of these same patients are now approaching clinics around the world offering experimental stem cell-based interventions instead of waiting for scientists in the US to complete clinical trials. How did the same groups who were once the strongest supporters of stem cell research become stem cell tourists? And how can scientists, clinicians, and regulators work to bring stem cell patients back home to the US and into the clinical trial process?DiscussionIn this paper, we argue that the continued marketing and use of experimental stem cell-based interventions is problematic and unsustainable. Central problems include the lack of patient protection, US liability standards, regulation of clinical sites, and clinician licensing. These interventions have insufficient evidence of safety and efficacy; patients may be wasting money and time, and they may be forgoing other opportunities for an intervention that has not been shown to be safe and effective. Current practices do not contribute to scientific progress because the data from the procedures are unsuitable for follow-up research to measure outcomes. In addition, there is no assurance for patients that they are receiving the interventions promised or of what dosage they are receiving. Furthermore, there is inconsistent or non-existent follow-up care. Public policy should be developed to correct the current situation.ConclusionThe current landscape of stem cell tourism should prompt a re-evaluation of current approaches to study cell-based interventions with respect to the design, initiation, and conduct of US clinical trials. Stakeholders, including scientists, clinicians, regulators and patient advocates, need to work together to find a compromise to keep patients in the US and within the clinical trial process. Using HIV/AIDS and breast cancer advocate cases as examples, we identify key priorities and goals for this policy effort. (shrink)

Stem cells and the emerging field of regenerative medicine are at the frontiers of modern medicine. These areas of scientific inquiry suggest that in the future, damaged tissue and organs might be repaired through personalized cell therapy as easily as the body repairs itself, revolutionizing the treatment of numerous diseases. Yet the use of stem cells is fraught with ethical and public policy dilemmas that challenge scientists, clinicians, the public health community, and people of good will (...) everywhere. How shall we deal with these amazing biomedical advances, and how can we talk about potential breakthroughs with both moral and scientific intelligence? This book provides an innovative look at these vexing issues through a series of innovative Socratic dialogues that elucidate key scientific and ethical points in an approachable manner. Addressing the cultural and value issues underlying stem cell research while also educating readers about stem cells' biological function and medical applications, _Stem Cell Dialogues_ features fictional characters engaging in compelling inquiry and debate. Participants investigate the scientific, political, and socioethical dimensions of stem cell science using actual language, analysis, and arguments taken from scientific, philosophical, and popular literature. Each dialogue centers on a specific, recognizable topic, such as the policies implemented by the George W. Bush administration restricting the use of embryonic stem cells; the potential role of stem cells in personalized medicine; the ethics of cloning; and the sale of eggs and embryos. Additionally, speakers debate the use of stem cells to treat paralysis, diabetes, stroke effects, macular degeneration, and cancer. Educational, entertaining, and rigorously researched, _Stem Cell Dialogues_ should be included in any effort to help the public understand the science, ethics, and policy concerns of this promising field. (shrink)

In December 1998, two groups of scientists announced that they had successfully isolated and cultured human pluripotent stem cells. This news was greeted with both tremendous enthusiasm and concern. Because these cells can develop into most types of cells or tissues in the human body, they hold great promise for scientific research and medical advances. For example, stem cells can potentially be used to:Generate cells and tissues for transplantation and therapy for conditions such (...) as Parkinson’s disease, spinal cord injury, stroke, burns, heart disease, diabetes, and arthritis;Improve scientists’ understanding of the complex events that occur during normal human development, as well as the abnormal events which cause conditions such as birth defects and cancer; andSubstantially change the development and testing of drugs. New medications could be tested initially on stem cells, and only drugs which were safe and effective on the cells would be tested further on laboratory animals and humans. (shrink)

Stem cells and their malignant counterparts require the support of a specific microenvironment or “niche”. While various anti‐cancer therapies have been broadly successful, there are growing opportunities to target the environment in which these cells reside to further improve therapeutic efficacy and outcome. This is particularly true when the aim is to target normal or malignant stem cells. The field aiming to target or use the niches that harbor, protect, and support stem (...) class='Hi'>cells could be designated as “nichotherapy”. In this essay, we provide a few examples of nichotherapies. Some have been employed for decades, such as hematopoietic stem cell mobilization, whereas others are emerging, such as chemosensitization of leukemia stem cells by targeting their niche. (shrink)

Stem cells and their malignant counterparts require the support of a specific microenvironment or “niche”. While various anti‐cancer therapies have been broadly successful, there are growing opportunities to target the environment in which these cells reside to further improve therapeutic efficacy and outcome. This is particularly true when the aim is to target normal or malignant stem cells. The field aiming to target or use the niches that harbor, protect, and support stem (...) class='Hi'>cells could be designated as “nichotherapy”. In this essay, we provide a few examples of nichotherapies. Some have been employed for decades, such as hematopoietic stem cell mobilization, whereas others are emerging, such as chemosensitization of leukemia stem cells by targeting their niche. (shrink)

This academic paper on Ethical issues of using umbilical cord blood stem cell therapy of John Stuart Mill perspective aim to investigate the new approaches in the treatment of diseases by using umbilical cord blood stem cells. And also to study ethical issues from the use of umbilical cord blood stem cells in the treatment of diseases considered by Mill’s utilitarianism. 21st century, the medical industry was interested in organ transplantation from stem cells (...) especially stem cells from the umbilical cord to treat chronic and degenerative organ diseases, blood cancer and organ transplantation which successful and widespread throughout the world. Thailand has about 900 new children with Leukemia every year. About 50 percent are leukemia which needs to be treated correctly and urgently. In general Standardized chemotherapy but if the cancer patient has a bad prognosis Or have recurrent cancer Patients need to be treated with bone marrow transplants or stem cells to have a chance to heal. According to Mill’s Utilitarianism, the ethical concepts that determine what is the basic criterion used to determine whether it should or should not concern with the popular benefit that the criterion used is the amount of happiness that results from actions. Treating the disease using stem cells will make the patient recover from the disease, healthier and happier in life. As Mill said "The correctness of an action depends on the tendency that the action will lead to happiness. (shrink)

The demonstration that pluripotent stem cells could be generated by somatic cell reprogramming led to wonder if these so-called induced pluripotent stem (iPS) cells would extend our investigation capabilities in the cancer research field. The first iPS cells derived from cancer cells have now revealed the benefits and potential pitfalls of this new model. iPS cells appear to be an innovative approach to decipher the steps of cell transformation as well as (...) to screen the activity and toxicity of anticancer drugs. A better understanding of the impact of reprogramming on cancer cell-specific features as well as improvements in culture conditions to integrate the role of the microenvironment in their behavior may strengthen the epistemic interest of iPS cells as model systems in oncology. (shrink)

This essay examines the role of social interactions in the search for blood stem cells, in a recent episode of biomedical research. Linked to mid-20th century cell biology, genetics and radiation research, the search for blood stem cells coalesced in the 1960s and took a developmental turn in the late 1980s, with significant ramifications for immunology, stem cell and cancer biology. Like much contemporary biomedical research, this line of inquiry exhibits a complex social structure (...) and includes several prominent scientific successes, recognized as such by participating researchers. I use personal interviews and the published record to trace the social interactions crucial for scientific success in this episode. All recognized successes in this episode have two aspects: improved models of blood cell development, and new interfaces with other lines of research. The narrative of the search for blood stem cells thus yields a robust account of scientific success in practice, which generalizes to other scientific episodes and lends itself to expansion to include wider social contexts. (shrink)

Cells can transit between a range of stable epithelial and mesenchymal states and this has allowed the evolution of complex body forms. Epithelial to mesenchymal transition (EMT) and its reverse, mesenchymal to epithelial transition (MET), occur sequentially in development and organogenesis. EMT often accompanies transitions between stem‐like cells and their more differentiated progeny, as occurs at gastrulation, although the relevance of this had not been clarified. New findings from the cancer and cell reprogramming fields suggest that (...) EMT and MET can act as essential portals to stem cell character. Here, we review these findings in the broader context of EMT and MET with emphasis on stem cell biology. Using the heart as an example, we also explore the potential role of EMT/MET in organ regeneration. Understanding EMT and MET at a network level will give us new tools to probe stem cell character and enhance tissue repair. (shrink)

Human pluripotent stem cells (hPSCs) have the potential to fundamentally change the way that we go about treating and understanding human disease. Despite this extraordinary potential, these cells also have an innate capability to form tumors in immunocompromised individuals when they are introduced in their pluripotent state. Although current therapeutic strategies involve transplantation of only differentiated hPSC derivatives, there is still a concern that transplanted cell populations could contain a small percentage of cells that are not (...) fully differentiated. In addition, these cells have been frequently reported to acquire genetic alterations that, in some cases, are associated with certain types of human cancers. Here, we try to separate the panic from reality and rationally evaluate the true tumorigenic potential of these cells. We also discuss a recent study examining the effect of culture conditions on the genetic integrity of hPSCs. Finally, we present a set of sensible guidelines for minimizing the tumorigenic potential of hPSC‐derived cells. © 2016 The Authors. Inside the Cell published by Wiley Periodicals, Inc. (shrink)

After a long and successful career in tracheal surgery and lung cancer, Paolo Macchiarini became very famous in 2008 with the transplantation of a trachea from a cadaver that then apparently used the patient’s own stem cells to supposedly regenerate new trachea, i.e., tissue-engineered tracheae. Among the nine patients that received this revolutionary treatment, using biological or artificial tracheae, under Macchiarini’s supervision, six have reportedly died. Although several critics had expressed concerns with the procedures, allegations of misconduct (...) against Macchiarini first arose in August of 2014 by four Karolinska Institutet (KI) colleagues, and an independent investigation was called for by KI based on claims made in seven published papers. Among the claims were the fact that the procedure constituted a high risk, information on the patients was incomplete and that there was no or incomplete ethical approval, thus constituting misconduct. His CV was also shown to contain inaccuracies. By September 10, 2016, most of these claims have now proved to be true, and Macchiarini was found guilty of misconduct by KI. This paper looks primarily at earlier published papers by Macchiarini and his collaborators in a search for clues to better understand the evolution of altruism, or narcissism. An assessment of the controversial papers, and of letters written by critics and skeptics like Pierre R. Delaere, indicate that insufficient experimental evidence was presented for several case studies, and that claims made about the success of the procedures exceeded what was shown by the evidence. A domino effect of personal and professional tragedies ensued, in rapid succession, between 2014 and 2016. The effect on the field of stem cell research has been chilling, and the side-effects have taken their toll, with several high-profile resignations, primarily at KI, within the Swedish education system and in the Nobel Committee. This case has mesmerized the bioethics and biomedical communities for years. (shrink)

Stem cell science, using both embryonic and a variety of tissue-specific stem cells, is advancing rapidly and offers promise to improve medical care in the future. Yet, with the notable exception of hematopoietic stem cell transplantation, a long-established approach to treating certain cancers of the blood system, this promise is long term and most stem cell research focuses on basic scientific questions or the collection of pre-clinical data. Although some clinical trials are underway, most are (...) focused on safety, and novel effective therapy is likely a long way off. Despite the preliminary nature of most stem cell research, however, numerous clinics around the world offer stem cell “therapies” to patients today outside the context of a clinical trial. Although the number of patients who have received these stem cell-based interventions is unknown, anecdotal reports suggest a substantial population of patients is willing to try them, despite unresolved questions about their safety and efficacy. (shrink)

Balancing self‐renewal and differentiation of stem cells is an important issue in stem cell and cancer biology. Recently, the Drosophila neuroblast (NB), neural stem cell has emerged as an excellent model for stem cell self‐renewal and tumorigenesis. It is of great interest to understand how defects in the asymmetric division of neural stem cells lead to tumor formation. Here, we review recent advances in asymmetric division and the self‐renewal control of Drosophila NBs. (...) We summarize molecular mechanisms of asymmetric cell division and discuss how the defects in asymmetric division lead to tumor formation. Gain‐of‐function or loss‐of‐function of various proteins in the asymmetric machinery can drive NB overgrowth and tumor formation. These proteins control either the asymmetric protein localization or mitotic spindle orientation of NBs. We also discuss other mechanisms of brain tumor suppression that are beyond the control of asymmetric division. (shrink)

Elizabeth H. Blackburn, Ph.D., is a leader in the area of telomere and telomerase research—in fact, in 1984 she codiscovered the ribonucleoprotein enzyme telomerase, opening up new potentials in cancer research and therapy. This and subsequent work has earned her numerous honors, not the least of which are the National Academy of Science Award in Molecular Biology, an Honorary Doctorate of Science from Yale University, the American Cancer Society Medal of Honor, and many more awards. Dr. Blackburn is (...) a Fellow of the American Academy of Arts and Sciences, the Royal Society of London, the American Academy of Microbiology, and the American Association for the Advancement of Science. She was elected to the National Academy of Sciences, and is a Member of the Institute of Medicine. (shrink)

Hepatocellular carcinoma represents the third leading cause of cancer-related death. Because HCC is multicentric with time, excluding the few transplanted patients, sooner or later it becomes untreatable with loco-regional therapies and, until some years ago, it was not responsive to systemic therapies. In 2005 a randomized trial indicated the efficacy of a product containing stem cell differentiation stage factors taken from zebrafish embryos during the stage in which the totipotent stem cells are differentiating into the pluripotent (...) adult stem cells. In such a trial the patients, with “intermediate” and “advanced” HCC according to Barcelona Clinic Liver Cancer/American Association for the Study of Liver Diseases guidelines, presented benefit in terms of performance status and objective tumoral response, with some cases of complete response, that is, sustained disappearance of the neoplastic areas or blood supply therein, accompanied by normalization of alpha-fetoprotein... (shrink)

BackgroundSocial support plays an important role for health outcomes. Support for those living with chronic conditions may be particularly important for their health, and even for their survival. The role of support for the survival of cancer patients after receiving an allogeneic hematopoietic cell transplant is understudied. To better understand the link between survival and support, as well as different sources and functions of support, we conducted two studies in alloHCT patients. First, we examined whether social support is related (...) to survival. Second, we examined who provides which support and which specific support-related functions and tasks are fulfilled by lay caregivers and healthcare professionals.MethodsIn Study 1, we conducted a retrospective chart review of alloHCT patients and registered availability of a dedicated lay caregiver and survival. In Study 2, we prospectively followed patients after alloHCT from the same hospital, partly overlapping from Study 1, who shared their experiences of support from lay caregivers and healthcare providers in semi-structured in-depth interviews 3 to 6 months after their first hospital discharge.ResultsPatients with a dedicated caregiver had a higher probability of surviving to 100 days than patients without a caregiver, OR = 2.84, p = 0.042. Study 2 demonstrated the importance of post-transplant support due to patients’ emotional needs and complex self-care regimen. The role of lay caregivers extended to many areas of patients’ daily lives, including support for attending doctor’s appointments, managing medications and financial tasks, physical distancing, and maintaining strict dietary requirements. Healthcare providers mainly fulfilled medical needs and provided informational support, while lay caregivers were the main source of emotional and practical support.ConclusionThe findings highlight the importance of studying support from lay caregivers as well as healthcare providers, to better understand how they work together to support patients’ adherence to recommended self-care and survival. (shrink)

On the basis of the evidence that tumor development is suppressed by the embryonic microenvironment, some experiments using the factors taken from Zebrafish embryo at precise stages of cell differentiation were made. These experiments demonstrated a significant growth inhibition on different tumor cell lines in vitro. The observed mechanism of tumor growth inhibition is connected with the key-role cell cycle regulation molecules, such as p53 and pRb, which are modified by transcriptional or post-translational processes. Research on apoptosis and differentiation revealed (...) that treatment with these factors induces caspase-3 with a p73 apoptotic-dependent pathway activation and a concurrent significant normalization of e-cadherin and beta-catenin ratio. Other experiments found a synergistic effect on the colon cancer proliferation curve after the concurrent treatment with these factors and 5-fluorouracil. Finally, a product prepared for human therapy demonstrated 19.8% regression and 16% stable disease in an... (shrink)

The YAP/TAZ family of transcriptional co‐activators drives cell proliferation in epithelial tissues and cancers. Yet, how YAP and TAZ are physiologically regulated remains unclear. Here we review recent reports that YAP and TAZ act primarily as sensors of epithelial cell polarity, being inhibited when cells differentiate an apical membrane domain, and being activated when cells contact the extracellular matrix via their basal membrane domain. Apical signalling occurs via the canonical Crumbs/CRB‐Hippo/MST‐Warts/LATS kinase cascade to phosphorylate and inhibit YAP/TAZ. Basal (...) signalling occurs via Integrins and Src family kinases to phosphorylate and activate YAP/TAZ. Thus, YAP/TAZ is localised to the nucleus in basal stem/progenitor cells and cytoplasm in differentiated squamous cells or columnar cells. In addition, other signals such as mechanical forces, tissue damage and possibly receptor tyrosine kinases (RTKs) can influence MST‐LATS or Src family kinase activity to modulate YAP/TAZ activity. (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)

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)

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)

B‐cell acute lymphoblastic leukaemia (B‐ALL) is a clonal malignant disease originated in a single cell and characterized by the accumulation of blast cells that are phenotypically reminiscent of normal stages of B‐cell differentiation. B‐ALL origin has been a subject of continuing discussion, given the fact that human disease is diagnosed at late stages and cannot be monitored during its natural evolution from its cell of origin, although most B‐ALLs probably start off with chromosomal changes in haematopoietic stem (...) class='Hi'>cells. However, the cells responsible for maintaining the disease appear to differ between the different types of B‐ALLs and this remains an intriguing and exciting topic of research, since these cells have been posited to be responsible for resistance to conventional therapies, recurrence and dissemination. During the last years this problem has been addressed primarily by transplantation of purified subpopulations of human B‐ALL cells into immunodeficient mice. The results from these different reconstitution experiments and their interpretations are compared in this review in the context of normal B‐cell developmental plasticity. While the results from different research groups might appear mutually exclusive, we discuss how they could be reconciled with the biology of normal B‐cells and propose research avenues for addressing these issues in the future. (shrink)

Parallels between cancer and ecological systems have been increasingly recognized and extensively reviewed. However, a more unified framework of understanding cancer as an evolving dynamical system that undergoes a sequence of interconnected changes over time, from a dormant microtumor to disseminated metastatic disease, still needs to be developed. Here, we focus on several examples of such mechanisms, namely, how in cancer niche construction a metabolic adaptation and consequent change to the tumor microenvironment becomes an important factor in (...) evasion of the predator, facilitating disease progression; how tumor establishment and propagation is driven by the tumor’s own keystone species, the cancer stem cells; and how the succession of stages of metastatic dissemination can be informed by ergodic theory and forest ecology. (shrink)

This paper explores the epistemology of extrapolation from model organisms to humans in molecular medicine. We take into account two common views on the issue, the homology view and the disanalogy view. In response to both interpretations, we argue that the foundational basis of extrapolations cannot simply be provided by homology and that relevant disanalogies can, thanks to the techniques of molecular biology, be experimentally controlled and exploited to allow useful and reliable extrapolations. The case of "humanised mice" in the (...) context of cancer stem cell research provides evidence of how animal models can be construed to approximate bona fide causal analogue models of human diseases. To supplement this view we show how the epistemology of model organisms needs to take into account the engineering side of molecular medicine. Model organisms are often manipulated to create analogies or remove disanalogies with the target system. We maintain that highlighting this feature is fundamental to explain what warrants extrapolation in the search for the molecular causes of disease. (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)

In 2015, Tomasetti and Vogelstein published a paper in Science containing the following provocative statement: “… only a third of the variation in cancer risk among tissues is attributable to environmental factors or inherited predispositions. The majority is due to “bad luck,” that is, random mutations arising during DNA replication in normal, noncancerous stem cells.” The paper—and perhaps especially this rather coy reference to “bad luck”—became a flash point for a series of letters and reviews, followed by (...) replies and yet further counterpoints. In this paper, I critically assess Tomasetti and Vogelstein's argument, discuss the meaning of “luck” (or, better: “chance”) in the context of the debate, and use this case study to address larger questions about methodological criteria for causal explanations of population level patterns in biomedicine. (shrink)

We are essentially a society of cells that come from a single cell, the fertilised egg. Research in cell biology has made major advances that are relevant to medicine and our understanding of life. Our understanding of the role of genes and proteins is impressive. But is this science dangerous? The whole of Western literature has not been kind to cell scientists and is filled with images of scientists meddling with nature, with disastrous results.1 Just consider Shelley’s Frankenstein, Goethe’s (...) Faust and Huxley’s Brave New World. One will search with very little success for a novel in which scientists come out well—the persistent image is that of scientists as a group unconcerned with ethical issues.There is a fear and distrust of cell science, particularly genetic engineering, leading to genetically modified foods, genetic modification of humans, cloning and stem cells. There is something of a revulsion in humankind’s meddling with nature and a longing for a Rousseauish-like return to golden age of innocence. There is anxiety that scientists lack both wisdom and social responsibility and are so motivated by ambition that they will follow their research anywhere, no matter what the consequences. Scientists are repeatedly referred to as “playing God”. Many of these criticisms coexist with the hope, particularly in medicine, that science will provide cures to all major illnesses, such as cancer, heart disease and genetic disabilities such as cystic fibrosis. But is cell science dangerous and what are the special social responsibilities of scientists? It is worth noting one irony: although scientists are blamed for making us live in a high-risk society, it is only because of science that we know about these risks, such as those related to health.The media must bear much of the responsibility for the misunderstanding of genetics as genetic pornography is, …. (shrink)

Graphical AbstractCancer is a complex disease, with sophisticated cellular mechanisms as the targets of evolutionary processes driven by random genetic and epigenetic mutations. Oncogenesis is evolutionarily linked to stem cell numbers/mutations and organ/body size; therefore, inter-disciplinary frameworks across different scales (cellular, tissue, organs and species) are necessary to decipher cancer progression.

Reprogramming technologies show that cellular identity can be reprogrammed, challenging the classical conception of cell differentiation as an irreversible process. If non-stem cells can be reprogrammed into stem cells, then what is it to be a stem cell, and what kind of property is stemness? This article addresses this question both philosophically and biologically, states the different possibilities, and illustrates their potential consequences for science with the example of anti-cancer therapies.

Despite the extensive literature describing the somatic genetic alterations in cancer cells, the precise origins of cancer cells remain controversial. In this article, I suggest that the etiology of cancer and the generation of genetic instability in cancer cells should be considered in the light of recent findings on both the stochastic nature of gene expression and its regulation at tissue level. By postulating that gene expression is intrinsically probabilistic and that stabilization of (...) gene expression arises by cellular interactions in “morphogenetic fields”, development and cellular differentiation can be rethought in an evolutionary perspective. In particular, this article proposes that disruptions of cellular interactions are the initial source of abnormal gene expression in cancer cells. Consequently, cancer phenotypes such as genetic and epigenetic instabilities, and also the presence of cells with stem cell‐like properties, may result from inaccurate and aberrant patterns of gene expression generated by microenvironmental alterations. Finally, the therapeutic implications of this view are discussed. BioEssays 27:1277–1285, 2005. © 2005 Wiley Periodicals, Inc. (shrink)

Once regarded as cellular ‘debris’ extracellular vesicles (EVs) emerge as one of the most intriguing entities in cancer pathogenesis. Intercellular trafficking of EVs challenges the notion of cancer cell autonomy, and highlights the multicellular nature of such fundamental processes as stem cell niche formation, tumour stroma generation, angiogenesis, inflammation or immunity. Recent studies reveal that intercellular exchange mediated by EVs runs deeper than expected, and includes molecules causative for cancer progression, such as oncogenes (epidermal growth factor (...) receptor, Ras), and tumour suppressors (PTEN). The uptake of oncogenic EVs (oncosomes) by various cells may profoundly change their biology, signalling patterns and gene expression, and in some cases cause their overt tumorigenic conversion. Moreover, EVs circulating in blood and present in body fluids provide an unprecedented access to the molecular circuitry driving cancer cells, and new technologies are being developed to exploit this property as a source of unique cancer biomarkers. (shrink)