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)

Endosteal stem cells are a subclass of bone marrow skeletal stem cell populations that are particularly important for rapid bone formation occurring in growth and regeneration. These stem cells are strategically located near the bone surface in a specialized microenvironment of the endosteal niche. These stem cells are abundant in young stages but eventually depleted and replaced by other stem cell types residing in a non‐endosteal perisinusoidal niche. Single‐cell molecular profiling and in vivo cell lineage analyses play key roles in (...) discovering endosteal stem cells. Importantly, endosteal stem cells can transform into bone tumor‐making cells when deleterious mutations occur in tumor suppressor genes. The emerging hypothesis is that osteoblast‐chondrocyte transitional identities confer a special subset of endosteal stromal cells with stem cell‐like properties, which may make them susceptible for tumorigenic transformation. Endosteal stem cells are likely to represent an important therapeutic target of bone diseases caused by aberrant bone formation. (shrink)

Tumour‐associated genetic changes frequently involve DNA translocation or deletion. Many of these events will have arisen from initial genomic damage, induced by either the activity of endogenous metabolic processes or from exposure to environmental genotoxic agents. Although initial genomic damage will have been widely distributed, tumorigenic events are confined to certain DNA target sites. Furthermore, within these target sites there appear to be regions of preferential DNA rearrangement, and examination of these sites implies that the location and extent of such (...) rearrangement may be influenced by DNA primary and secondary structure rather than simply by the point of damage. We selectively review evidence relating to DNA structures that may predispose certain regions of the genome to damage‐induced rearrangement, and discuss the possible role of interstitial, inverted telomere‐like sequence arrays in promoting chromosomal events of a type known to be associated with some human and animal tumours. (shrink)

Illuminating insights into lymphoid oncogenesis came with the finding that the chromosome translocations characteristic of many tumors of immunoglobulin‐producing cells represent conjunction of an immunoglobulin gene locus with the myc oncogene. The potency of this combination has been underlined by recent studies in which DNA regions mimicking certain chromosome junctions of lymphomas were shown to be highly tumorigenic when inserted into the mouse germline. Nevertheless, the mechanism by which an immunoglobulin locus activates the oncogene remains largely an enigma, particularly in (...) those cases where the two loci remain at some distance. (shrink)

Human cancers comprise an heterogeneous array of diseases with different progression patterns and responses to therapy. However, they all develop within a host context that constrains their natural history. Since it occurs across the diversity of organisms, one can conjecture that there is order in the cancer multiverse. Is there a way to capture the broad range of tumor types within a space of the possible? Here we define the oncospace, a coordinate system that integrates the ecological, evolutionary and developmental (...) components of cancer complexity. The spatial position of a tumor results from its departure from the healthy tissue along these three axes, and progression trajectories inform about the components driving malignancy across cancer subtypes. We postulate that the oncospace topology encodes new information regarding tumorigenic pathways, subtype prognosis, and therapeutic opportunities: treatment design could benefit from considering how to nudge tumors toward empty evolutionary dead ends in the oncospace. (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)

Despite decades of research, remaining safety concerns regarding disease transmission, heterotopic tissue formation, and tumorigenicity have kept stem cell‐based therapies largely outside the standard‐of‐care for musculoskeletal medicine. Recent insights into trophic and immune regulatory activities of mesenchymal stem cells (MSCs), although incomplete, have stimulated a plethora of new clinical trials for indications far beyond simply supplying progenitors to replenish or re‐build lost/damaged tissues. Cell banks are being established and cell‐based products are in active clinical trials. Moreover, significant advances have (...) also been made in the field of pluripotent stem cells, in particular the recent development of induced pluripotent stem cells. Their indefinite proliferation potential promises to overcome the limited supply of tissue‐specific cells and adult stem cells. However, substantial hurdles related to their safety must be overcome for these cells to be clinically applicable. (shrink)

The integrated stress response (ISR) is a key determinant of tumorigenesis in response to oncogenic forms of stress like genotoxic, proteotoxic and metabolic stress. ISR relies on the phosphorylation of the translation initiation factor eIF2 to promote the translational and transcriptional reprogramming of gene expression in stressed cells. While ISR promotes tumor survival under stress, its hyperactivation above a level of tolerance can also cause tumor death. The tumorigenic function of ISR has been recently demonstrated for lung adenocarcinomas (LUAD) with (...) KRAS mutations. ISR mediates the translational repression of the dual‐specificity phosphatase DUSP6 to stimulate ERK activity and LUAD growth. The significance of this finding is highlighted by the strong anti‐tumor responses of ISR inhibitors in pre‐clinical LUAD models. Elucidation of the mechanisms of ISR action in LUAD progression via cell‐autonomous and immune regulatory mechanisms will provide a better understanding of its tumorigenic role to fully exploit its therapeutic potential in the treatment of a deadly form of cancer. (shrink)

Genome instability has been associated with progression of transformed cells to high tumorigenicity. Although genome instability may result from a variety of factors, some studies suggest that DNA in the region of a chromosome rearrangement can subsequently have much higher rates of DNA deletions or gene amplification. One approach to studying the factors that produce these high rates of DNA rearrangement is by analysis of unstable integration sites for DNA transfected into mammalian cells. Integrated sequences commonly show a temporary (...) instability, and at rare locations this instability is continuous and can be observed even after multiple subclonings. These continuously unstable locations undergo DNA amplification of both the integrated sequences and the surrounding cell DNA, and it can occur either at the original site or on episomes after looping out from the chromosome. Because the adjacent cell DNA plays a role in this instability, and the region can be shown to be stable before integration, the results indicate that these recombinational hotspots can be formed de novo by the process of integration. Current studies are attempting to determine which sequences are responsible for the high rates of recombination and whether similar types of event are involved in the instability associated with endogenous cellular genes in cancer cells. (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)

The highly structured mechanisms of cancers, their tendency to occur as a response to environmental stress, and the existence of oncogenes, suggest that neoplasticity may represent more than a biological disfunction. It is proposed that cancer exists as a phylogenetic mechanism serving to promote hyperevolution, albeit at the expense of the ontogeny, that is similar to a process recently discovered in bacterial mutations. Cell-surface-associated nucleic acid in tumorigenic cells and sperm cell vectorization of foreign DNA indicate the existence of essential (...) mechanisms necessary to the occurrence of cancer mediated hyperevolution. An analysis of the proposed mechanism indicates that for mutagenesis of chemical cytology, stress induced neoplasticity confers an evolutionary advantage of more than two orders of magnitude. (shrink)

Apoptosis‐inducing factor (AIF) is expelled from mitochondria after some apoptotic stimuli and translocates to the nucleus, which may contribute to DNA and nuclear fragmentation in some non‐physiological mammalian cell deaths. Conversely, the requirement for mitochondrial AIF in oxidative phosphorylation and energy generation provides a plausible explanation for the embryonic lethality or neurodegeneration that has been found in different AIF‐deficient mouse models. These findings may help illuminate the ability of mitochondrial AIF to suppress cytoplasmic stress granule formation and to promote the (...) tumorigenic growth of cancer cells. AIF is ideally located in the mitochondrion to perform a vital normal function in energy production. Once it translocates to the nucleus, however, the cell might die either of energy failure or nuclear fragmentation (or both). We propose that the main function of AIF is to support energy production in both normal and transformed cell physiology, whereas nuclear‐translocated AIF might contribute to stress‐induced or pathological cell death in certain scenarios. BioEssays 28: 834–843, 2006. © 2006 Wiley Periodicals, Inc. (shrink)

Genes that exert their function when they are introduced into a foreign genetic background pose many questions to our current understanding of the forces and mechanisms that promote either the maintenance or divergence of gene functions over evolutionary time. The melanoma inducing Xmrk oncogene of the Southern platyfish (Xiphophorus maculatus) is a stable constituent of the genome of this species. It displays its tumorigenic function, however, almost exclusively only after inter‐populational or, even more severely, interspecific hybridization events. The Xiphophorus hybrid (...) melanoma system has gained attention in biomedical research as a genetic model for studying tumor formation. From an evolutionary perspective, a prominent question is: how could this gene persist over millions of years? An attractive hypothesis is that Xmrk, acting as a detrimental gene in a hybrid genome, could be a speciation gene that shields the gene pool of its species from mixing with other closely related sympatric species. In this article, I briefly review our current knowledge of the molecular genetics and biochemical functions of the Xmrk gene and discuss aspects of its evolutionary history and presence with respect to this idea. While Xmrk as a potentially injurious oncogene has clearly survived for millions of years, its role as a speciation gene has to be questioned. BioEssays 30:822–832, 2008. © 2008 Wiley Periodicals, Inc. (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)

Human induced pluripotent stem cells can be obtained from somatic cells, and their derivation does not require destruction of embryos, thus avoiding ethical problems arising from the destruction of human embryos. This type of stem cell may provide an important tool for stem cell therapy, but it also results in some ethical concerns. It is likely that abnormal reprogramming occurs in the induction of human induced pluripotent stem cells, and that the stem cells generate tumors in the process of stem (...) cell therapy. Human induced pluripotent stem cells should not be used to clone human beings, to produce human germ cells, nor to make human embryos. Informed consent should be obtained from patients in stem cell therapy. (shrink)