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In defense of the Somatic Mutation Theory of Cancer
Abstract
According to the somatic mutation theory (SMT), cancer begins with a genetic change in a single cell that passes it on to its progeny, thereby generating a clone of malignant cells. It is strongly supported by observations of leukemias that bear specific chromosome translocations, such as Burkitt's lymphoma, in which a translocation activates the c-myc gene, and chronic myeloid leukemia (CML), in which the Philadelphia chromosome causes production of the BCR-ABL oncoprotein. Although the SMT has been modified and extended to encompass tumor suppressor genes, epigenetic inheritance, and tumor progression through accumulation of further mutations, perhaps the strongest validation comes from the successful treatment of certain malignancies with drugs that directly target the product of the mutant gene.
David Vaux is at the Walter and Eliza Hall Institute and La Trobe Institute for Molecular Science, Melbourne, Australia
... The interest in radiation-induced nuclear DNA damage stems from the most widespread mechanistic model of carcinogenesis, the more-than-a-century-old somatic mutation theory (Boveri 1914, Hanahan and Weinberg 2000, 2011, Vaux 2011, which posits that genetic alterations or mutations can lead to carcinogenesis. DNA damage clusters are pertinent in the radiation context because they rarely occur via endogenous processes but can be effectively induced by ionizing radiation. ...
... The interest in radiation-induced nuclear DNA damage stems from the most widespread mechanistic model of carcinogenesis, the more-than-a-century-old somatic mutation theory (Boveri 1914, Hanahan and Weinberg 2000, 2011, Vaux 2011, which posits that genetic alterations or mutations can lead to carcinogenesis. DNA damage clusters are pertinent in the radiation context because they rarely occur via endogenous processes but can be effectively induced by ionizing radiation. ...
... The extracted damage yields were normalized to the dose and to the total number of base pairs in our DNA model (6.3 Gbp). The mean values obtained across 100 independent runs were then benchmarked against published data from simulated proton irradiations (Nikjoo et al 2001, Friedland et al 2003, 2011 (Roots and Okada 1972, Chapman et al 1973, Roots and Okada 1975, Frankenberg et al 1999, Belli et al 2000, Campa et al 2005. The standard uncertainty of the mean for each set of runs was also calculated. ...
The risk of radiobiological stochastic effects associated with neutrons is strongly energy dependent. Recent Monte Carlo studies simulating neutron-irradiated nuclear DNA have demonstrated that this energy dependence is correlated with the relative biological effectiveness (RBE) of neutrons to inflict DNA damage clusters that contain difficult-to-repair double-strand breaks. However, these previous investigations were either limited to modeling direct radiation action or considered the effects of both direct and indirect action together without distinguishing between the two. In this study, we aimed to quantify the influence of indirect action in neutron irradiation scenarios and acquire novel estimations of the energy-dependent neutron RBE for inducing DNA damage clusters due to both direct and indirect action.
Approach: We explored the role of indirect action in neutron-induced DNA damage by integrating a validated indirect action model into our existing simulation pipeline. Using this pipeline, we performed track-structure simulations of monoenergetic neutron irradiations (1 eV to 10 MeV) in a nuclear DNA model and analyzed the resulting simple and clustered DNA lesions. We repeated the irradiation simulations for 250 keV X-rays that acted as our reference radiation.
Main results: Including indirect action significantly increased the occurrence of DNA lesions. We found that indirect action tends to amplify the damage due to direct action by inducing DNA lesions in the vicinity of directly-induced lesions, resulting in additional and larger damage clusters. Our neutron RBE results are qualitatively similar to but lower in magnitude than the established radiation protection factors and the results of previous similar investigations, due to the greater relative impact of indirect action in photon-induced damage than in neutron-induced damage.
Significance: Although our model for neutron-induced DNA damage has some important limitations, our findings suggest that the energy-dependent risk of neutron-induced stochastic effects may not be completely modeled alone by the relative potential of neutrons to inflict clustered lesions via direct and indirect action in DNA damage.
... It follows that the hallmarks of cancer (2) derive from successive mutations producing advantageous biological capabilities, in a multistep process of tumor development. This widely accepted theory explains many cancer features, from hereditary cancers to successful therapies targeting the product of mutant genes (1). But there are also many important events that are contradictory to its predictions and some ad-hoc modifications must be introduced to explain them, leading to serious inconsistencies. ...
... But there are also many important events that are contradictory to its predictions and some ad-hoc modifications must be introduced to explain them, leading to serious inconsistencies. There are many reports of zero mutations found in some tumors (3), whereas malignant properties are a result of changes in the DNA methylation pattern and not in its sequence (1). Additionally, there are a few non-genotoxic carcinogens, like chloroform and p-dichlorobenzene (4), which induce cancer without direct modifications to DNA. ...
... Stem and cancer cells' phenotypes share some similarities, the two being in a proliferative state, are invasive and can be considered potentially immortal (22). Also they both show self-renewal capability and block differentiation (22); they are primitive and undifferentiated (1,23). Our hypothesis is then that carcinogenesis can be due to resurrection of an early stem cell-like behavior, with expression of stem cell transcription factors, in an inappropriate location and time (22). ...
Even if the Somatic Mutation Theory of carcinogenesis explains many of the relevant experimental results in tumor origin and development, there are frequent events that are not justified, or are even contradictory to this widely accepted theory. A Cell Reversal Theory is presented, putting forward the hypothesis that cancer is originated by reversal of a differentiated cell into a non-differentiated stem-like state, by a change of its intrinsic epigenetic state, following a perturbation on the cell and/or its microenvironment. In the current proposal a cluster of cancer stem cells can be established, without the strict control mechanisms of a normal stem cell niche, and initiate a tumor. It is proposed that a reversal to a pluripotent state is at tumor origin and not tumor progress that prompts cell dedifferentiation. The uncontrolled proliferation of cancer stem cells causes a microenvironment disorganization, resulting in stressful conditions, like hypoxia and nutrient deprivation, which induces the genetic instability characteristic of a tumor; thus, in most cases, mutations are a consequence and not the direct cause of a tumor. It is also proposed that metastases result from dedifferentiation signaling dispersion instead of cell migration. However, conceivably, once the microenvironment is normalized, the stem cell-like state can differentiate back to a mature cell state and loose its oncogenic capacity. Therefore, this can be a reversible condition, suggesting important therapeutic opportunities.
... This genetic hypothesis of carcinogenesis has first been postulated in 1914, more than 100 years ago, by Theodor Boveri [Boveri T, 1914]. While during the rest of 20th century this paradigm dominated cancer research and still does [Vaux, 2011], experimental and clinical evidence repeatedly casted serious doubt on it [Sonnenschein et al., 2014;Brücher and Jamall, 2016]. For instance, SMT considers cancer as a cell-based disease triggered by crucial mutations in 'driver' genes such as oncogenes and/or tumor suppressor genes rendering the affected somatic parenchyma cell more autonomous in growth and less dependent from surrounding non-transformed mesenchymal stroma cells (the 'genetic code of cancer'). ...
... cell anchoring via intercellular contact/extracellular matrix/basement membrane) interaction between epithelial parenchyma and mesenchymal stroma cells, which leads to derangement of tissue organization causing metaplasia, dysplasia and neoplastic transformation irrespective of the occurrence of mutations. Thus, while in SMT the founding event is an alteration in the DNA of the transforming cell [Vaux, 2011], in TOFT the causative mechanism of transformation is a deviation in the transcellular organization and interaction leading to an altered architecture of the host tissue compartments no matter if the affected cells are mutated or not [Soto and Sonnenschein, 2011]. At first glance the two paradigms appear rather incompatible. ...
Here we contrast several carcinogenesis models. The somatic-mutation-theory posits mutations as main causes of malignancy. However, inconsistencies led to alternative explanations. For example, the tissue-organization-field-theory considers disrupted tissue-architecture as main cause. Both models can be reconciled using systems-biology-approaches, according to which tumors hover in states of self-organized criticality between order and chaos, are emergent results of multiple deviations and are subject to general laws of nature: inevitable variation(mutation) explainable by increased entropy(second-law-of-thermodynamics) or indeterminate decoherence upon measurement of superposed quantum systems(quantum mechanics), followed by Darwinian-selection. Genomic expression is regulated by epigenetics. Both systems cooperate. So cancer is neither just a mutational nor an epigenetic problem. Rather, epigenetics links environmental cues to endogenous genetics engendering a regulatory machinery that encompasses specific cancer-metabolic-networks. Interestingly, mutations occur at all levels of this machinery (oncogenes/tumor-suppressors, epigenetic-modifiers, structure-genes, metabolic-genes). Therefore, in most cases, DNA mutations may be the initial and crucial cancer-promoting triggers.
... This simple pipeline where molecular defects are pharmacologically targeted works strikingly well in the context of some cancers (Vaux 2011), and in some rare monogenic disorders. For example, a gene-targeted drug treatment (costing ∼ 750,000 -2,125,000 US dollars (Darrow et al. 2020)) can alters abnormal splicing of the SMN1 gene and practically cure spinal muscular atrophy, a debilitating pediatric neuromuscular disorder (Mullard 2017). ...
... In comparison, our maternally and paternally inherited germline variants are set at the time of conception, subsequently layered with the accumulation of somatic nuclear and mitochondrial gene mutations. It is widely believed that de novo mutations may contribute to some cancers (Vaux 2011), but gene mutations may otherwise have limited specific biological effects (Robinson et al. 2021;Versteeg 2014) and even have anti-neoplastic effects in some contexts (Colom et al. 2021). Therefore, our genes change little over time, and mostly in one direction (accumulating mutations of uncertain significance), yet our health is highly changeable-capable of declining and improving over short and long periods of time. ...
Modern Western biomedical research and clinical practice are primarily focused on disease. This disease-centric approach has yielded an impressive amount of knowledge around what goes wrong in illness. However, in comparison, researchers and physicians know little about health. What is health? How do we quantify it? And how do we improve it? We currently do not have good answers to these questions. Our lack of fundamental knowledge about health is partly driven by three main factors: (i) a lack of understanding of the dynamic processes that cause variations in health/disease states over time, (ii) an excessive focus on genes, and (iii) a pervasive psychological bias towards additive solutions. Here I briefly discuss potential reasons why scientists and funders have generally adopted a gene- and disease-centric framework, how medicine has ended up practicing “diseasecare” rather than healthcare, and present cursory evidence that points towards an alternative energetic view of health. Understanding the basis of human health with a similar degree of precision that has been deployed towards mapping disease processes could bring us to a point where we can actively support and promote human health across the lifespan, before disease shows up on a scan or in bloodwork.
... The somatic mutation theory of carcinogenesis (Hanahan and Weinberg 2000, 2011, Vaux 2011) posits that genomic mutations can lead to carcinogenesis and is perhaps the most longstanding mechanistic theory of carcinogenesis. Nowadays, it is generally believed that radiation can induce mutagenesis via several pathways, including both nuclear DNA damage and non-targeted effects (Iyer andLehnert 2000, Little 2000). ...
... The somatic mutation theory of carcinogenesis (Hanahan and Weinberg 2000, 2011, Vaux 2011) posits that genomic mutations can lead to carcinogenesis and is perhaps the most longstanding mechanistic theory of carcinogenesis. Nowadays, it is generally believed that radiation can induce mutagenesis via several pathways, including both nuclear DNA damage and non-targeted effects (Iyer andLehnert 2000, Little 2000). ...
Neutron exposure poses a unique radiation protection concern because neutrons have a large, energy-dependent relative biological effectiveness (RBE) for stochastic effects. Recent computational studies on the microdosimetric properties of neutron dose deposition have implicated clustered DNA damage as a likely contributor to this marked energy dependence. So far, publications have focused solely on neutron RBE for inducing clusters of DNA damage containing two or more DNA double strand breaks (DSBs). In this study, we have conducted a novel assessment of neutron RBE for inducing all types of clustered DNA damage that contain two or more lesions, stratified by whether the clusters contain DSBs (complex DSB clusters) or not (non-DSB clusters). This assessment was conducted for eighteen initial neutron energies between 1 eV and 10 MeV as well as a reference radiation of 250 keV x-rays. We also examined the energy dependence of cluster length and cluster complexity because these factors are believed to impact the DNA repair process. To carry out our investigation, we developed a user-friendly TOPAS-nBio application that includes a custom nuclear DNA model and a novel algorithm for recording clustered DNA damage. We found that neutron RBE for inducing complex DSB clusters exhibited similar energy dependence to the canonical neutron RBE for stochastic radiobiological effects, at multiple depths in human tissue. Qualitatively similar results were obtained for non-DSB clusters, although the quantitative agreement was lower. Additionally we identified a significant neutron energy dependence in the average length and complexity of clustered lesions. These results affirm that many types of clustered DNA damage contribute to the energy dependence of neutron RBE for stochastic radiobiological effects and that the size and constituent lesions of individual clusters should be taken into account when modeling DNA repair. Our results were qualitatively consistent for (i) multiple radiation doses (including a low dose 0.1 Gy irradiation), (ii) variations in the maximal lesion separation distance used to define a cluster, and (iii) two distinct collections of physics models used to govern particle transport. Our complete TOPAS-nBio application has been released under an open source license to enable others to independently validate our work and to expand upon it.
... A mature understanding of causation is essential for transitioning basic knowledge into biomedical progress, which relies on identification of causes for disease conditions, and for the development of effective therapies that restore physiological or structural states. For example, the debate on the causal nature of mutations in carcinogenic dysregulation [1][2][3][4] is focused on the question of what actually induces cells to abandon the bodyplan and revert to a unicellular-like existence, and what intervention might be sufficient to induce a rescue. ...
... [8][9][10][11][12][13][14] However, numerous fields of the life sciences are now facing a turning point that indicates the need for a paradigm shift toward a more mature understanding of causation in evolutionary, developmental, and biomedical contexts. This is largely due to five major developments: 1) the advent of novel technologies that provide an unprecedented amount of observational and experimental "Big Data" sets that reveal the incredibly tangled details underlying system-level outcomes in biological systems, 2) developments in network science and information theory that provide new mathematical approaches that extract rich control structures from biological data, 3) an increasing awareness of the presence and importance of variability, stochasticity, heterogeneity, and noise, 4) a pressing need to translate successes in molecular-level processes into biomedically important anatomical outcomes, and 5) a breaking down of the barriers between the study of life as it is (the zoology of existing model systems) and "life as it could be" (Artificial Life in silico and in vitro [15] ). While technology is constantly improving in spatial and temporal resolution, providing ever more drill-down toward molecularlevel events, researchers are tackling increasingly larger questions about control and dynamics of global patterning under a variety of perturbations. ...
Evolution exploits the physics of non-neural bioelectricity to implement anatomical homeostasis: a process in which embryonic patterning, remodeling, and regeneration achieve invariant anatomical outcomes despite external interventions. Linear "developmental pathways" are often inadequate explanations for dynamic large-scale pattern regulation, even when they accurately capture relationships between molecular components. Biophysical and computational aspects of collective cell activity toward a target morphology reveal interesting aspects of causation in biology. This is critical not only for unraveling evolutionary and developmental events, but also for the design of effective strategies for biomedical intervention. Bioelectrical controls of growth and form, including stochastic behavior in such circuits, highlight the need for the formulation of nuanced views of pathways, drivers of system-level outcomes, and modularity, borrowing from concepts in related disciplines such as cybernetics, control theory, computational neuroscience, and information theory. This approach has numerous practical implications for basic research and for applications in regenerative medicine and synthetic bioengineering.
... Historically, this view has been called the Somatic Mutation Theory (Vaux, 2011) or the oncogene paradigm (Plutynski, 2018b). Cancer researchers today recognize that multiple factors influence the proliferation of cancer cells (Weinberg, 2007;Hanahan & Weinberg, 2011), but most research efforts still focus on genetic factors and molecular pathways as targets of intervention and explanation. ...
... Hence, the results of such experiments cannot be informative of the relative importance or (ir)relevance of biomechanical factors as these are excluded from the outset of the analysis. As mentioned, genetic difference-making is often studied through 2D cultures of cell populations with controlled and modified gene expression, e.g., via gene knock-out experiments (Vaux, 2011). Such studies, together with more recent tumor sequencing projects, have no doubt shed light on important genetic markers and pathways involved in carcinogenesis. ...
Discussions about reductionism and downward causation are often assumed to be primarily of interest to philosophers. Often, however, the question of whether multi-scale systems can be understood “bottom-up” has important practical implications for scientific inquiry. Cancer research, I argue, is one such example. While the focus on genetic factors has intensified with recent investments in cancer genomics, the importance of biomechanical factors within the tumor microenvironment is increasingly acknowledged. I suggest that role of solid-state tissue properties in tumor progression can be interpreted as a form of downward causation, understood as constraining relations between tissue-scale and micro-scale variables. Experimental demonstrations of these sort of influences reveal limitations of reductionist accounts and expose the dangers of what Wimsatt calls functional localization fallacies. The latter relate to the common bias of downgrading factors that – as a practical necessity – are left out of scientific analysis. Any heuristic, experimental or theoretical, involves foregrounding some aspects while ignoring others, and the complexity of cancer leaves room for the co-existence of many different partial perspectives. These perspectives are not reducible to one another, but neither do they in this case make up a neatly integrated “causal mosaic” of different influences. At present, the picture of cancer research looks more like a fragmented cubist painting in need of a more balanced attention to difference-making factors at higher levels or scales.
... Historically, this view has been called the Somatic Mutation Theory (Vaux, 2011) or the oncogene paradigm (Plutynski, 2018b). Cancer researchers today recognize that multiple factors influence the proliferation of cancer cells (Weinberg, 2007;Hanahan & Weinberg, 2011), but most research efforts still focus on genetic factors and molecular pathways as targets of intervention and explanation. ...
... Hence, the results of such experiments cannot be informative of the relative importance or (ir)relevance of biomechanical factors as these are excluded from the outset of the analysis. As mentioned, genetic difference-making is often studied through 2D cultures of cell populations with controlled and modified gene expression, e.g., via gene knock-out experiments (Vaux, 2011). Such studies, together with more recent tumor sequencing projects, have no doubt shed light on important genetic markers and pathways involved in carcinogenesis. ...
Discussions about reductionism and downward causation are often assumed to be primarily of interest to philosophers. Often, however, the question of whether multi-scale systems can be understood "bottom-up" has important practical implications for scientific inquiry. Cancer research, I argue, is one such example. While the focus on genetic factors has intensified with recent investments in cancer genomics, the importance of biomechanical factors within the tumor microenvironment is increasingly acknowledged. I suggest that role of solid-state tissue properties in tumor progression can be interpreted as a form of downward causation, understood as constraining relations between tissue-scale and micro-scale variables. Experimental demonstrations of these sort of influences reveal limitations of reductionist accounts and expose the dangers of what Wimsatt calls functional localization fallacies. The latter relate to the common bias of downgrading factors that-as a practical necessity-are left out of scientific analysis. Any heuristic, experimental or theoretical, involves foregrounding some aspects while ignoring others, and the complexity of cancer leaves room for the coexistence of many different partial perspectives. These perspectives are not reducible to one another, but neither do they in this case make up a neatly integrated "causal mosaic" of different influences. At present, the picture of cancer research looks more like a fragmented cubist painting in need of a more balanced attention to difference-making factors at higher levels or scales.
... Then, under natural selection in the cell population, those cells carrying mutations that confer a "fitter" phenotype would clonally expand, with the "fittest" clone (derived from a single cell) eventually taking over the population. This Neo-Darwinian scheme is applied to tumors in a loose, qualitative, if not figurative manner [96], often departing from rigorous concepts of evolutionary biology, and eventually becoming known as the SMT [97]. The idea of SMT has its origin in 1914 when the embryologist Theodor Boveri proposed that cancer originates from chromatin alterations in a cell. ...
Genome sequencing of cancer and normal tissues, alongside single-cell transcriptomics, continues to produce findings that challenge the idea that cancer is a ‘genetic disease’, as posited by the somatic mutation theory (SMT). In this prevailing paradigm, tumorigenesis is caused by cancer-driving somatic mutations and clonal expansion. However, results from tumor sequencing, motivated by the genetic paradigm itself, create apparent ‘paradoxes’ that are not conducive to a pure SMT. But beyond genetic causation, the new results lend credence to old ideas from organismal biology. To resolve inconsistencies between the genetic paradigm of cancer and biological reality, we must complement deep sequencing with deep thinking: embrace formal theory and historicity of biological entities, and (re)consider non-genetic plasticity of cells and tissues. In this Essay, we discuss the concepts of cell state dynamics and tissue fields that emerge from the collective action of genes and of cells in their morphogenetic context, respectively, and how they help explain inconsistencies in the data in the context of SMT.
... The dominant theory of carcinogenesis is more than 100 years old and is known as the somatic mutation theory (SMT) (Barrett 1993). It directly links mutagenesis, which is the process of the formation of mutations in the DNA molecules of somatic cells, to the development of cancer (Vaux 2011). The SMT postulates that DNA mutations in a single cell can cause neoplastic transformation of that cell, resulting in uncontrolled growth of the cell and subsequent tumour formation. ...
The Linear No-Threshold (LNT) model was introduced into the radiological protection system about 60 years ago, but this model and its use in radiation protection are still debated today. This article presents an overview of results on effects of exposure to low linear-energy-transfer (LET) radiation in radiobiology and epidemiology accumulated over the last decade and discusses their impact on the use of the LNT model in the assessment of radiation-related cancer risks at low doses. The knowledge acquired over the past 10 years, both in radiobiology and epidemiology, has reinforced scientific knowledge about cancer risks at low doses. In radiobiology, although certain mechanisms do not support linearity, the early stages of carcinogenesis comprised of mutational events, which are assumed to play a key role in carcinogenesis, show linear responses to doses from as low as 10 mGy. The impact of non-mutational mechanisms on the risk of radiation-related cancer at low doses is currently difficult to assess. In epidemiology, the results show excess cancer risks at dose levels of 100 mGy or less. While some recent results indicate non-linear dose relationships for some cancers, overall, the LNT model does not substantially overestimate the risks at low doses. Recent results, in radiobiology or in epidemiology, suggest that a dose threshold, if any, could not be greater than a few tens of mGy. The scientific knowledge currently available does not contradict the use of the LNT model for the assessment of radiation- related cancer risks within the radiological protection system, and no other dose-risk relationship seems more appropriate for radiological protection purposes.
... The somatic mutation theory teaches that cancer begins with a genetic change in a single cell which passes it on to its progeny, thereby generating a clone of malignant cells. 1 In addition to somatic mutation, first proposed by Boveri in 1914, non-genomic properties of the cancer cell, some referred to as hallmarks, have also been identified as part of the cancer phenotype. As well as somatic mutations which drive oncogenesis, the cancer cell expresses a range of disparate characteristics including the avoidance of apoptosis, reliance on aerobic glycolysis and Cdk4 overexpression. ...
Background
Normal adult mammalian cells can respond to oncogenic somatic mutations by committing suicide through a well‐described, energy dependent process termed apoptosis. Cancer cells avoid oncogene promoted apoptosis. Oncogenic somatic mutations are widely acknowledged to be the cause of the relentless unconstrained cell proliferation which characterises cancer. But how does the normal cell with the very first oncogenic mutation survive to proliferate without undergoing apoptosis?
New findings
The phenomena of malignant transformation by somatic mutation, apoptosis, aneuploidy, aerobic glycolysis and Cdk4 upregulation in carcinogenesis have each been extensively discussed separately in the literature but an overview explaining how they may be linked at the initiation of the cancer process has not previously proposed.
Conclusion
A hypothesis is presented to explain how in addition to the initial oncogenic mutation, the expression of certain key normal genes is, counter‐intuitively, also required for successful malignant transformation from a normal cell to a cancer cell. The hypothesis provides an explanation for how the cyclic amphiphilic peptide HILR‐056, derived from peptides with homology to a hexapeptide in the C‐terminal region of Cdk4, kill cancer cells but not normal cell by necrosis rather than apoptosis.
... The mechanisms of GBM initiation and expansion are still unclear. Tumor initiation may result from normal neural stem cells accumulating oncogenic mutations that transform these cells into cancer stem-like cells capable of generating cancer cell subclones [54][55][56]. An alternative theory, based on Paget's "seed and soil" hypothesis and demonstrated by many studies, states that tumor initiation and expansion are held silent until a permissive environment is generated [57][58][59]. ...
Glioblastoma (GBM) is the most common and most aggressive primary brain tumor in adults. Glioma stem like cells (GSC) represent the highest cellular hierarchy in GBM and have a determining role in tumor growth, recurrence and patient prognosis. However, a better definition of GSC subpopulations, especially at the surgical resection margin, is warranted for improved oncological treatment options. The present study interrogated cells expressing CD105 (CD105 ⁺ ) specifically within the tumor front and the pre-invasive niche as a potential GSC subpopulation. GBM primary cell lines were generated from patients (n = 18) and CD105 ⁺ cells were isolated and assessed for stem-like characteristics. In vitro, CD105 ⁺ cells proliferated and enriched in serum-containing medium but not in serum-free conditions. CD105 ⁺ cells were characterized by Nestin ⁺ , Vimentin ⁺ and SOX2 ⁻ , clearly distinguishing them from SOX2 ⁺ GCS. GBM CD105 ⁺ cells differentiated into osteocytes and adipocytes but not chondrocytes. Exome sequencing revealed that GBM CD105 ⁺ cells matched 83% of somatic mutations in the Cancer cell line encyclopedia, indicating a malignant phenotype and in vivo xenotransplantation assays verified their tumorigenic potential. Cytokine assays showed that immunosuppressive and protumorigenic cytokines such as IL6, IL8, CCL2, CXCL-1 were produced by CD105 ⁺ cells. Finally, screening for 88 clinical drugs revealed that GBM CD105 ⁺ cells are resistant to most chemotherapeutics except Doxorubicin, Idarubicin, Fludarabine and ABT-751. Our study provides a rationale for targeting tumoral CD105 ⁺ cells in order to reshape the tumor microenvironment and block GBM progression.
... Last but not least, regarding the ongoing debate on the origin of cancer (such as between the proponents of the somatic mutation theory (SMT) [132] on the one side and those of the tissue organization field theory (TOFT) [133] on the other side, as well as the atavistic theory by Davies and Lineweaver [134]), there are obstacles that limit the interpretation power of the approach presented here. Firstly, the molecular cause of cancer can vary. ...
The exploitation of the evolutionary modus operandi of cancer to steer its progression towards drug sensitive cancer cells is a challenging research topic. Integrating evolutionary principles into cancer therapy requires properly identified selection level, the relevant timescale, and the respective fitness of the principal selection unit on that timescale. Interpretation of some features of cancer progression, such as increased heterogeneity of isogenic cancer cells, is difficult from the most straightforward evolutionary view with the cancer cell as the principal selection unit. In the paper, the relation between the two levels of intratumour heterogeneity, genetic, due to genetic instability, and non-genetic, due to phenotypic plasticity, is reviewed and the evolutionary role of the latter is outlined. In analogy to the evolutionary optimization in a changing environment, the cell state dynamics in cancer clones are interpreted as the risk diversifying strategy bet hedging, optimizing the balance between the exploitation and exploration of the cell state space.
... The clonal architecture of ALL was investigated by single cell analysis with multicolor probes for mutant genes. The data reveal not a linear sequence of mutation acquisition by clonal succession, but considerable complexity with a tree-like or branching structure of genetically [3] distinct subclones, very reminiscent of Darwin's original 1837 evolutionary divergence diagram [5]. On the other hand, Darwinian SMT cannot help sporadic carcinomas. ...
... Several theories have been suggested to explain carcinogenesis, The most popular of them is somatic mutation theory (SMT) 3 . However, this theory cannot explain most cancer scenarios 4 . Also, the vast amount of data obtained by cancer genome projects has not changed clinical practice 5 . ...
Cancer is among the most important public health problems. Despite advancements in medical technology, there is no significant reduction in cancer deaths. The most important reason for this is that there is no valid theory about carcinogenesis. Currently, studies on cancer are based on somatic mutation theory. However, many studies have shown that the somatic mutation theory is insufficient in explaining the development and progression of cancer. In recent years, Complex adaptive system theory and the chaotic behavior of these systems have recently become the main focus of interdisciplinary research in social and natural sciences. I attempted to explain carcinogenesis based on chaotic behavior, information and adaptation, and this opinion about carcinogenesis may offers a different perspective on cancer research. Genome recommends but environment makes the appropriate choice
... Fully differentiated cells can also de-differentiate and become more stem-cell-like. [37,63] As a result, neoplasms contain an anomalous proportion of immature cells. [12,15,64] This observation forms the basis of the cancer stem cell (CSC) hypothesis, [15,20,65,66] which led to the discovery of genetic signatures shared by cancer and embryonic stem cells. ...
It has long been recognized that cancer onset and progression represent a type of reversion to an ancestral quasi‐unicellular phenotype. This general concept has been refined into the atavistic model of cancer that attempts to provide a quantitative analysis and testable predictions based on genomic data. Over the past decade, support for the multicellular‐to‐unicellular reversion predicted by the atavism model has come from phylostratigraphy. Here, we propose that cancer onset and progression involve more than a one‐off multicellular‐to‐unicellular reversion, and are better described as a series of reversionary transitions. We make new predictions based on the chronology of the unicellular‐eukaryote‐to‐multicellular‐eukaryote transition. We also make new predictions based on three other evolutionary transitions that occurred in our lineage: eukaryogenesis, oxidative phosphorylation and the transition to adaptive immunity. We propose several modifications to current phylostratigraphy to improve age resolution to test these predictions.
... Several theories have been suggested to explain carcinogenesis, The most popular of them is somatic mutation theory (SMT) 3 . However, this theory cannot explain most cancer scenarios 4 . Also, the vast amount of data obtained by cancer genome projects has not changed clinical practice 5 . ...
Cancer is among the most important public health problems. Despite advancements in medical technology, there is no significant reduction in cancer deaths. The most important reason for this is that there is no valid theory about carcinogenesis. Currently, studies on cancer are based on somatic mutation theory. However, many studies have shown that the somatic mutation theory is insufficient in explaining the development and progression of cancer. In recent years, Complex adaptive system theory and the chaotic behavior of these systems have recently become the main focus of interdisciplinary research in social and natural sciences. I attempted to explain carcinogenesis based on chaotic behavior, information and adaptation, and this opinion about carcinogenesis may offers a different perspective on cancer research. Genome recommends but environment makes the appropriate choice
... However, it should be emphasized that most cancers are histopathologically diverse and contain cytologically different clones resulting from genetic transformation from one transformed cell. It also seems that mutational changes are generally insufficient to cause cancer, because only a small proportion of cancers, in about 5%, arise as a result of mutations [2]. The theory of somatic mutations has never been able to explain how non-mutagenic factors are responsible for carcinogenesis. ...
One of the most intriguing problems in biomedical sciences is the theory explaining cancer formation. It is known that cancer is the result of many molecular processes, the presence of oncogenic factors and the loss of apoptosis of affected cells. We currently have hypotheses based on carcinogenesis because of a single cell gene mutation, i.e. somatic mutation theory (SMT), or disorders in tissue architecture and intercellular communication called (TOFT) Tissue Organization Field Theory. An attempt to combine these separate and compatible cause and effect pathways into one unified theory of cancer transformation is the theory of chaotic adaptation. The new interpretative model is the systemic-evolution theory of cancer (SETOC) which postulates disintegration between the symbiosis of "energy" and "information" in normal cells. There are also epidemiological studies confirming that some types of cancer arise from viral infection. So, let us ask the question, can one hypothesis explain all the features of cancer?
... The current standard theory to explain tumorigenesis is the Somatic Mutation Theory (SMT) [1,2], which proposes 27 that the origin of cancer can be interpreted by an accumulation of genetic mutations, in particular on tumor 28 suppressor genes and oncogenes, that are passed to their cell descendants. Tumor development is then a multistep model represents a single layer tissue, in the 2 dimensional version, or a volumetric tissue, with the three dimen- ...
As the main theory of carcinogenesis, the Somatic Mutation Theory, increasingly presents difficulties to explain some experimental observations, different theories are being proposed. A major alternative approach is the Tissue Organization Field Theory, which explains cancer origin as a tissue regulation disease instead of having a mainly cellular origin. This work fits in the latter hypothesis, proposing the bioelectric field, in particular the cell membrane polarization state, and ionic exchange through ion channels and gap junctions, as an important mechanism of cell communication and tissue organization and regulation. Taking into account recent experimental results and proposed bioelectric models, a computational model of cancer initiation was developed, including the propagation of a cell depolarization wave in the tissue under consideration. Cell depolarization leads to a change in its state, with the activation and deactivation of several regulation pathways, increasing cell proliferation and motility, changing its epigenetic state to a more stem cell-like behavior without the requirement of genomic mutation. The intercellular communication via gap junctions leads, in certain circum stances, to a bioelectric state propagation to neighbor cells, in a chain-like reaction, till an electric discontinuity is reached. However, this is a reversible process, and it was shown experimentally that, by implementing a therapy targeted on cell ion exchange channels, it is possible to reverse the state and repolarize cells. This mechanism can be an important alternative way in cancer prevention, diagnosis and therapy, and new experiments are proposed to test the presented hypothesis.
... Cancer is the uncontrolled tissue growth that disrupts normal body functions. According to the somatic mutation theory, cancer begins with genetic mutations in a single cell that disrupt cell cycle regulations, which eventually leads to cancer [3]. However, some researchers dispute the supposed chronological order between somatic mutations and cancer. ...
In this paper, we introduce a new dataset for cancer research containing somatic mutation states of 536 genes of the Cancer Gene Census (CGC). We used somatic mutation information from the Cancer Genome Atlas (TCGA) projects to create this dataset. As preliminary investigations, we employed machine learning techniques, including k-Nearest Neighbors, Decision Tree, Random Forest, and Artificial Neural Networks (ANNs) to evaluate the potential of these somatic mutations for classification of cancer types. We compared our models on accuracy, precision, recall, and F1-score. We observed that ANNs outperformed the other models with F1-score of 0.36 and overall classification accuracy of 40%, and precision ranging from 12% to 92% for different cancer types. The 40% accuracy is significantly higher than random guessing which would have resulted in 3% overall classification accuracy. Although the model has relatively low overall accuracy, it has an average classification specificity of 98%. The ANN achieved high precision scores (> 0.7) for 5 of the 33 cancer types. The introduced dataset can be used for research on TCGA data, such as survival analysis, histopathology image analysis and content-based image retrieval. The dataset is available online for download: https://kimialab.uwaterloo.ca/kimia/.
... • "SMT has been expanded and refined, to now be the generally accepted model for cancer development" [6] • "The paradigm of carcinogenesis as a process of mutation accumulation is now well established" [7]; ...
The well-known Somatic Mutation theory that played a fundamental role in cancer research for about a century, considers cancer as a result of k successive mutations. One of the theory cornerstones is believed to be mathematical. It is about the cancer incidence rate being the same as the hazard function of incidence probability distribution. Actually these functions are not equivalent, we show that in two ways-in a rigorous mathematical form and by means of simulation based on open-access epidemiological data. A new algorithm, using mortal and survival data, is proposed for calculating the probability density function of the cancer start time distribution.
... Somatic mutation theory (SMT) is the most popular theory [3]. Mutational changes generally would be insufficient to cause cancer, because a minority of cancers were only triggered by about 5% mutations [4]. Another alternative theory is Tissue Field Organization Theory (TOFT). ...
Cancer, a disease of multicellular organisms, probably developed almost immediately following the transition from unicellular to metazoan life, about one billion years ago. Great efforts have been made to understand the carcinogenesis for many years. In this paper, We tried to explain the cancer based on "chaos", "adaptation" and "information" with the context of new literature findings.
... Somatic mutation theory (SMT) is the most popular theory [3]. Mutational changes generally would be insufficient to cause cancer, because a minority of cancers were only triggered by about 5% mutations [4]. Another alternative theory is Tissue Field Organization Theory (TOFT). ...
We are trying to evolve CAT
... The main concept of this theory was that cancer should result from time-dependent accumulation of DNA mutations in a single cell. Accordingly, cancers were thought to be monoclonal, i.e., they were all considered to be derived from a single mutant cell, thereby generating a homogeneous tissue composed of malignant cells [11]. Simultaneously, some scientists thought that mutations occurred in DNA, but without causing cancer. ...
Cancer stem cells (CSCs) also known as cancer-initiating cells (CIC), are responsible for the sustained and uncontrolled growth of malignant tumors and are proposed to play significant roles in metastasis and recurrence. Several hypotheses have proposed that the events in either stem and/or differentiated cells, such as genomic instability, inflammatory microenvironment, cell fusion, and lateral gene transfer, should be considered as the possible origin of CSCs. However, until now, the exact origin of CSC has been obscure. The development of induced pluripotent stem cells (iPSCs) in 2007, by Yamanaka’s group, has been met with much fervency and hailed as a breakthrough discovery by the scientific and research communities, especially in regeneration therapy. The studies on the development of CSC from iPSCs should also open a new page of cancer research, which will help in designing new therapies applicable to CSCs. Currently most reviews have focused on CSCs and CSC niches. However, the insight into the niche before the CSC niche should also be of keen interest. This review introduces the novel concept of cancer initiation introducing the conversion of iPSCs to CSCs and proposes a relationship between the inflammatory microenvironment and cancer initiation as the key concept of the cancer-inducing niche responsible for the development of CSC. View Full-Text
Keywords: stem cell; cancer stem cells; induced pluripotent stem cells; cancer-inducing niche; chronic inflammation
... Programmed and non-programmed theories for aging have been compared by Goldsmith. The Somatic Mutation Theory (SMT) links cancer to somatic mutations accumulated with age [83]. For aging, a similar somatic mutation accumulation has been proposed [4,50,84]. ...
During evolution, Muller's ratchet permanently generates deleterious germline mutations that eventually must be defused by selection. It seems widely held that cancer and aging-related diseases (ARDs) cannot contribute to this germline gene selection because they tail reproduction and thus occur too late, at the end of the life cycle. Here we posit however that by lessening the offspring's survival by proxy through diminishing parental care, they can still contribute to the selection. The hypothesis in detail: The widespread occurrence of aging in animals suggests that it is an adaptation. But to what benefit? Aging seems to have only drawbacks. In humans, ARDs cause today almost all mortality; they include heart disease, cerebrovascular disease, Alzheimer's disease, kidney disease and cancer. Compensation seems unthinkable. For cancer, the author proposed in a previous study a benefit to the species: purifying selection against deleterious germline genes that when expressed enhance intracellular energy dissipation. This multicausal energy dissipation, posited as the universal origin of cancer initiation, relates to cellular heat generation, disrupted metabolism, and inflammation. The organism reproduces during cancer's dormancy, and when approaching its end of life, the onset of cancer is accelerated in proportion to the cancer-initiating signal. Through cancer, the organism, now a parent, implements the self-actuated programmed death of Skulachev's phenoptosis. This “first death” enhances by proxy the offspring's chance of “second death” (or “double death”) through diminished parental care. Repetition over generations realizes a purifying selection against genes causing energy dissipation. The removal of the deleterious germline gene mutations permanently generated by Muller's ratchet gives a benefit. We generalize, motivated by the parallels between cancer and aging, the purifying selection posited for cancer to aging. An ARD would be initiated in the organ by multicausal disruption of homeostasis, and be followed by dormancy and senescence until its onset near the end of the life cycle. Just as for cancer, the ARD eventually enhances double death, and the realized permanent selection gives a benefit to the species through the selection against germ line genes that disrupt homeostasis. Given their similarities, cancer and aging are combined in the posited Unified Cancer-Aging Adaptation (UCAA) model, which may be confirmed by next-generation sequencing data. Also because of the emerging important role of cellular senescence, the hypothesis may guide the development of therapies against both cancer and aging.
... The issue of whether and how an integration of these two diverging epistemic frameworks is possible is hotly debated by scientists and philosophers of biology. The earlier mostly tend to take side for one of the two (Vaux 2011;Bizzarri and Cucina 2016), while the philosophers-adept to thinking in terms of "pluralism of descriptive and explanatory accounts" (PhoC, p. 12)-rather to inquire on the conditions for their compatibility and eventual integration (Malaterre 2007;Bedessem and Ruphy 2015;Bertolaso and Dupré 2018). For Bertolaso, however, in the practice of science the divide between the two paradigms has already been challenged. ...
It is widely accepted that cancer mostly arises from random spontaneous mutations triggered by environmental factors. Our theory challenges the idea of the random somatic mutation theory (SMT). The SMT does not fit well with Charles Darwin’s theory of evolution in that the same relatively few mutations would occur so frequently and that these mutations would lead to death rather than survival of the fittest. However, it would fit well under the theory of evolution, if we were to look at it from the vantage point of pathogens and their supporting microbial communities colonizing humans and mutating host cells for their own benefit, as it does give them an evolutionary advantage and they are capable of selecting genes to mutate and of inserting their own DNA or RNA into hosts. In this article, we provide evidence that tumors are actually complex microbial communities composed of various microorganisms living within biofilms encapsulated by a hard matrix; that these microorganisms are what cause the genetic mutations seen in cancer and control angiogenesis; that these pathogens spread by hiding in tumor cells and M2 or M2-like macrophages and other phagocytic immune cells and traveling inside them to distant sites camouflaged by platelets, which they also reprogram, and prepare the distant site for metastasis; that risk factors for cancer are sources of energy that pathogens are able to utilize; and that, in accordance with our previous unifying theory of disease, pathogens utilize melanin for energy for building and sustaining tumors and metastasis. We propose a paradigm shift in our understanding of what cancer is, and, thereby, a different trajectory for avenues of treatment and prevention.
Multiple theories exist to explain cancer initiation, although a consensus on this is crucial for developing effective therapies. ‘Somatic mutation theory’ suggests that mutations in somatic cells during DNA repair initiates cancer but this concept has several attached paradoxes. Research efforts to identify quiescent cancer stem cells (CSCs) that survive therapy and result in metastasis and recurrence have remained futile. In solid cancers, CSCs are suggested to appear during epithelial-mesenchymal transition by the dedifferentiation and reprogramming of epithelial cells. Pluripotent and quiescent very small embryonic-like stem cells (VSELs) exist in multiple tissues but remain elusive owing to their small size and scarce nature. VSELs are developmentally connected to primordial germ cells, undergo rare, asymmetrical cell divisions and are responsible for the regular turnover of cells to maintain tissue homeostasis throughout life. VSELs are directly vulnerable to extrinsic endocrine insults because they express gonadal and gonadotropin hormone receptors. VSELs undergo epigenetic changes due to endocrine insults and transform into CSCs. CSCs exhibit genomic instability and develop mutations due to errors during DNA replication while undergoing excessive proliferation and clonal expansion to form spheroids. Thus tissue-resident VSELs offer a connection between extrinsic insults and variations in cancer incidence reported in various body tissues. To conclude, cancer is indeed a stem cell disease with mutations occurring as a consequence. In addition to immunotherapy, targeting mutations, and Lgr5 + organoids for developing new therapeutics, targeting CSCs (epigenetically altered VSELs) by improving their niche and epigenetic status could serve as a promising strategy to treat cancer.
Graphical Abstract
The global burden of cancer incidence, deaths and economic costs is steadily increasing since several decades. Despite a massive allocation of research funds since the 1970s, no significant (in terms of years) improvements of survival times have been achieved for most cancer types. In this article, I argue that the failure to effectively prevent and treat cancer is partly owing to the gene-centric paradigm of the somatic mutation theory of carcinogenesis. I outline and provide evidence for a new transdisciplinary evolutionary theory of carcinogenesis according to which cancer is a phylogenetic reversal towards unicellular lifeforms triggered by the breakdown of essential cooperative interactions on important levels of human organization. These levels include the genetic, cellular, tissue and psychosocial-spiritual level of human existence. The new theory considers the emergence of eukaryotes and metazoans and e of particular importance e human evolution and in this way explains why cooperation on these different levels is so essential to maintain holistic health. It is argued that the interaction between human's slow natural evolution and the fast cultural evolution, especially during the current Anthropocene epoch, plays an important role in making individuals susceptible towards carcinogenesis. The implications of this insight and the theory of cancer as a phylogenetic reversal are discussed with respect to prevention and treatment, and concrete practical examples are provided. It is concluded that individuals could substantially reduce their risk of cancer by respecting certain biopsychosocial-spiritual lifestyle factors which are justified by human evolution.
Le modèle linéaire sans seuil (LNT) a été introduit dans le système de radioprotection il y a environ 60 ans, mais ce modèle et son utilisation en radioprotection sont encore débattus aujourd'hui. Cet article résume les résultats en radiobiologie et en épidémiologie accumulés au cours de la dernière décennie sur les effets d’une exposition aux rayonnements ionisants à faible Transfert d’Energie Linéique (TEL) et discute de leur impact sur l'utilisation du modèle LNT dans l'évaluation des risques de cancer par rayonnement à faibles doses. Les connaissances acquises au cours des 10 dernières années, tant en radiobiologie qu'en épidémiologie, ont renforcé les fondements scientifiques sur les risques de cancer à faibles doses. En radiobiologie, bien que certains mécanismes ne soient pas linéaires avec la dose, les premiers stades de la cancérogenèse composés d'événements mutationnels, qui jouent un rôle clé dans la cancérogenèse, montrent des réponses linéaires à des doses aussi faibles que 10 mGy. L'impact des mécanismes non mutationnels sur le risque de cancer associé aux rayonnements à faibles doses est actuellement difficile à évaluer. En épidémiologie, les résultats montrent un excès de risques de cancer à des niveaux de dose de 100 mGy ou moins. Bien que certains résultats récents indiquent des relations non linéaires avec la dose pour certains types de cancers, le modèle LNT ne surestime pas substantiellement globalement les risques à faibles doses. Les résultats actuels, en radiobiologie ou en épidémiologie, ne démontrent pas l'existence d'un seuil de dose en dessous duquel le risque de cancer associé aux rayonnements serait nul. Des incertitudes persistent mais un tel seuil de dose, s'il existe, ne pourrait être supérieur à quelques dizaines de mGy. L'IRSN considère que les connaissances scientifiques actuellement disponibles ne remettent pas en cause l'utilisation du modèle LNT pour l'évaluation des risques de cancers radio-induits en appui au système de radioprotection. L'utilisation de ce modèle semble raisonnable d'un point de vue scientifique, et aucune autre relation dose-réponse ne semble plus adaptée ou justifiée à des fins de radioprotection.
Mutation accumulation in stem cells has been associated with cancer risk. However, the presence of numerous mutant clones in healthy tissues has raised the question of what limits cancer initiation. Here, we review recent developments in characterizing mutation accumulation in healthy tissues and compare mutation rates in stem cells during development and adult life with corresponding cancer risk. A certain level of mutagenesis within the stem cell pool might be beneficial to limit the size of malignant clones through competition. This knowledge impacts our understanding of carcinogenesis with potential consequences for the use of stem cells in regenerative medicine.
Cancer stem cells (CSCs) are a subclass of cancer cells that can differentiate into various cell types and self-renew, similar to normal stem cells. CSCs play an important role in the initiation and progression of cancer, and as such, there has been extensive research into the molecular and cellular mechanisms underlying the properties of CSCs and how they contribute to the development and spread of cancer. CSCs are thought to be responsible for cancer initiation because they can divide and differentiate into multiple cell types, allowing them to contribute to the formation of a malignant tumor. CSCs are also largely resistant to cancer therapies, which allows them to survive and continue to divide, leading to the growth and progression of the tumor. CSCs can migrate to other body parts and form new tumors, a process known as metastasis. This is one of the major challenges in treating cancer, as it is difficult to eliminate CSCs and prevent the spread of the disease. There is ongoing research into the molecular and cellular mechanisms underlying the properties of CSCs, as well as efforts to develop targeted therapies that specifically target CSCs to improve the treatment of cancer. Some potential therapeutic strategies include inhibiting the pathways that control the self-renewal and viability of CSCs or targeting the microenvironment that supports the growth and survival of CSCs.KeywordsCancer initiationProgressionMalignancyCancer stem cellSurvivalTargeted therapies
Cancer is a disease with a long history from prehistoric times that could be traced back to the era of dinosaurs. In humans, cancer becomes prevalent much more than ever due to the extension of average lifespan and the increase of exposure to carcinogenic factors in the environments during the last decades. Seven Egyptian papyri, which were the oldest in human history to introduce Egyptian medical practice, were found and deciphered in the late nineteenth century. “Edwin Smith” and “George Ebers” were the two papyri that contained the descriptions of cancer. They were estimated to be written between around 3000 to 1600 BC. Hippocrates (460–370 BC), the “Father of Medicine,” used the term “karkinos,” which means a crab in Greek, to describe the disease since a tumor with metastasis along with lymph nodes appeared like crab finger projections from the breast. And probably breast cancer cases were the easiest ones to find and diagnose at a glance.Since the beginning of cancer study, many theories about cancer have been proposed including humoral theory, lymph theory, blastema theory, chronic irritation theory, viral oncogenesis, chemical carcinogenesis, mutation theory, tissue organization field theory (TOFT), and cancer stem cell theory. In the current chapter, we highlight old observations, hypotheses, and practices in cancer research shaped as modern medicine during a couple of past decades with excerpts.KeywordsHumoral theoryLymph theoryBlastema theoryChronic irritation theoryViral & Chemical carcinogensStem cell
Recently many new causes of cancer have been recognized, such as Sunlight, tobacco, pharmaceuticals, hormones, alcohol, parasites, fungi, bacteria, salted fish, wood dust, and certain herbs. However, they are additional causes of cancer that contains beta carotene, red meat, processed meats, low intake of fiber diets, poor Exclusive Breast Feeding (EBF), obesity, increased adult height, sedentary lifestyles, etc.; there is a knowledge imbalance in knowing the causes of cancer among the physicians as well as researchers. To prevent at and permit the early detection and effective treatment is necessary in this regard. Steps were taken to prevent, control and management of cancer are disturbed by the insufficient knowledge about the disease among the population. The ultimate aim of cancer management is to reduce the prevalence of cancer and to improve the quality of life. A practical way to identify cancer control risk is to understand the real risk factors for causing cancer. When the causes are not well explained and understood, it is difficult to treat the disease. Screening of asymptomatic populations and awareness of early signs and symptoms can certainly improve the treatment of cancer. Knowing the causes of cancer and knowledge about preventing it can cure the disease, prolong our life, and improve the quality of our life. Cancer research is crucial for effective planning and strategic Cancer Control Programmes (CCP).
Ketogenic diets have been used to treat epilepsy for nearly a century. Alongside enduring clinical success with a ketogenic diet, metabolism’s critical role in health and in diseases in the central nervous system and throughout the body is increasingly appreciated. Furthermore, metabolism-based strategies have been proven equal or even superior to pharmacological treatments in specific cases and for specific diseases. Rather than causing unwanted off-target pharmacological side effects, addressing metabolic dysfunction can improve overall health simultaneously. Enduring interest in the ketogenic diet’s proven efficacy in stopping seizures and emerging efficacy in other disorders has fueled renewed efforts to determine key mechanisms and diverse applications of metabolic therapies. In parallel, multiple strategies are being developed to mobilize similar metabolic benefits without reliance on such a strict diet. Research interest in metabolic therapies has spread into laboratories and clinics of every discipline, and could yield entirely new classes of drugs and treatment regimens. This work is the first comprehensive scientific resource on the ketogenic diet, covering the latest research into the mechanisms, established and emerging applications, metabolic alternatives, and implications for health and disease. Experts in clinical and basic research share their research into mechanisms spanning from ion channels to epigenetics, their insights based on decades of experience with the ketogenic diet in epilepsy, and their evidence for emerging applications ranging from autism to Alzheimer’s disease to brain cancer.
Cancer is a genetic disease caused by mutations that arise in our genomic DNA. Specific types of mutations drive a lengthy evolutionary process that culminates in the formation of invasive tumors. A unifying concept known as the cancer gene theory explains how mutations arise in expanding cell populations and reveals why everyone is at risk of developing cancer. This powerful theoretical model explains why cancer is closely associated with aging, and also reveals why individuals in some families are predisposed to develop cancer earlier in life. The cancer gene theory provides insight into why cancers disproportionately arise in certain tissues and how environmental mutagens can profoundly increase our cancer risk.
Mounting evidence indicates that cancer is primarily a mitochondrial metabolic disease rather than a genetic disease. Abnormalities in cancer cell mitochondria impair oxidative phosphorylation, thus causing a gradual shift in cellular energy production from respiration to fermentation. Glucose and glutamine are the two major fermentable fuels for cancer cells. Glucose drives tumor growth through glycolysis in the cytoplasm, while glutamine drives tumor growth through glutaminolysis in the mitochondria. Restriction of fermentable fuels is therefore an effective therapeutic strategy for cancer management. Ketogenic metabolic therapy (KMT) lowers blood glucose while elevating blood ketone bodies, a “super fuel” for normal cells, but a nonfermentable fuel for cancer cells. The efficacy of KMT for cancer management can be enhanced when used together with glutamine-targeting drugs and procedures that further inhibit fermentation. Hence, KMT represents an alternative, nontoxic strategy for managing and preventing a broad range of cancers and could also be important in reducing healthcare costs in the emerging era of global budgeting.
Cancer is primarily a disease of dysregulation – both at the genetic level and at the tissue organization level. One way that tissue organization is dysregulated is by changes in the bioelectric regulation of cell signaling pathways. At the basis of bioelectricity lies the cellular membrane potential or Vmem, an intrinsic property associated with any cell. The bioelectric state of cancer cells is different from that of healthy cells, causing a disruption in the cellular signaling pathways. This disruption or dysregulation affects all three processes of carcinogenesis – initiation, promotion, and progression. Another mechanism that facilitates the homeostasis of cell signaling pathways is the production of extracellular vesicles (EVs) by cells. EVs also play a role in carcinogenesis by mediating cellular communication within the tumor microenvironment (TME). Furthermore, the production and release of EVs is altered in cancer. To this end, the change in cell electrical state and in EV production are responsible for the bioelectric dysregulation which occurs during cancer. This paper reviews the bioelectric dysregulation associated with carcinogenesis, including the TME and metastasis. We also look at the major ion channels associated with cancer and current technologies and tools used to detect and manipulate bioelectric properties of cells.
Cancer research has been largely focused on the cellular and molecular levels of investigation. Recent data show that not only the cell but also the extracellular matrix plays a major role in the progression of malignancy. In this way, the cells and the extracellular matrix create a specific local microenvironment that supports malignant development. At the same time, cancer implies a systemic evolution which is closely related to developmental processes and adaptation. Consequently, there is currently a real gap between the local investigation of cancer at the microenvironmental level, and the pathophysiological approach to cancer as a systemic disease. In fact, the cells and the matrix are not only complementary structures but also interdependent components that act synergistically. Such relationships lead to cell-matrix integration, a supracellular form of biological organization that supports tissue development. The emergence of this supracellular level of organization, as a structure, leads to the emergence of the supracellular control of proliferation, as a supracellular function. In humans, proliferation is generally involved in developmental processes and adaptation. These processes suppose a specific configuration at the systemic level, which generates high-order guidance for local supracellular control of proliferation. In conclusion, the supracellular control of proliferation act as an interface between the downstream level of cell division and differentiation, and upstream level of developmental processes and adaptation. Understanding these processes and their disorders is useful not only to complete the big picture of malignancy as a systemic disease, but also to open new treatment perspectives in the form of etiopathogenic (supracellular or informational) therapies.
As the main theory of carcinogenesis, the Somatic Mutation Theory, increasingly presents difficulties to explain some experimental observations, different theories are being proposed. A major alternative approach is the Tissue Organization Field Theory, which explains cancer origin as a tissue regulation disease instead of having a mainly cellular origin. This work fits in the latter hypothesis, proposing the bioelectric field, in particular the cell membrane polarization state, and ionic exchange through ion channels and gap junctions, as an important mechanism of cell communication and tissue organization and regulation. Taking into account recent experimental results and proposed bioelectric models, a computational model of cancer initiation was developed, including the propagation of a cell depolarization wave in the tissue under consideration. Cell depolarization leads to a change in its state, with the activation and deactivation of several regulation pathways, increasing cell proliferation and motility, changing its epigenetic state to a more stem cell-like behavior without the requirement of genomic mutation. The intercellular communication via gap junctions leads, in certain circumstances, to a bioelectric state propagation to neighbor cells, in a chain-like reaction, till an electric discontinuity is reached. However, this is a reversible process, and it was shown experimentally that, by implementing a therapy targeted on cell ion exchange channels, it is possible to reverse the state and repolarize cells. This mechanism can be an important alternative way in cancer prevention, diagnosis and therapy, and new experiments are proposed to test the presented hypothesis.
It is well accepted that the tumor microenvironment plays a pivotal role in cancer onset, development, and progression. The majority of clinical interventions are designed to target either cancer or stroma cells. These emphases have been directed by one of two prevailing theories in the field, the Somatic Mutation Theory and the Tissue Organization Field Theory, which represent two seemingly opposing concepts. This review proposes that the two theories are mutually inclusive and should be concurrently considered for cancer treatments. Specifically, this review discusses the dynamic and reciprocal processes between stromal cells and extracellular matrices, using pancreatic cancer as an example, to demonstrate the inclusivity of the theories. Furthermore, this review highlights the functions of cancer associated fibroblast, which represent the major stromal cell, as important mediators of the known cancer hallmarks that the two theories attempt to explain.
Total Marrow Irradiation (TMI) is an emerging, technologically advanced radiation conditioning regimen that can simultaneously delivery radiation to specific body structures with high hematological disease burden and reduce radiation to organs at risk in order to maintain function. The result is an extraordinary ability to modulate the radiation dose to a very large extended target through the body, effecting a paradigm shift in the treatment of hematological malignancies. However, the radiobiological relevance is beginning to emerge and will be a valuable step for advancing the clinical benefit of this new technology. Toward this goal, we address the pathology of hematological disease, the historical relevance of total body irradiation and its limitations that led to TMI development, and key factors that are associated with radiobiological assessment. Furthermore, a vision of the future of radiology is discussed, in which we are expected to achieve an improved understanding of the complex and extended nature of disease and its associated microenvironment.
The term “magic bullet” was introduced in 1900 by Paul Ehrlich who formed an idea that it could be possible to kill specific microbes (such as bacteria) that cause diseases without harming the body itself – chemical specificity – and his work led to the first antibiotic treatment of syphilis. Hope for chemically specific magic bullets would triumph again in the Precision Medicine Initiative launched in 2015. It is based on the dominant model of carcinogenesis – somatic mutation theory. It is a reductionist approach focused on the individual cell(s) and while progress has been made, this narrow approach has faced difficulties such as tumor heterogeneity and plasticity and development of tumor cell resistance. Similar problems have been observed in the field of synthetic biology where there have been ‘inexplicable” failures of molecular and genetic devices to function as designed when tested in vivo, i.e., a new context. What is missing is the intervention x context interaction where the abnormal (or synthetic) gene is the “intervention.” Conceptualizing cancer as a dynamic complex system that emerges from the microenvironment in which it is embedded can help explain these observations. If correct, this raises questions about the possibility of precision medicine for cancer and other conditions as well because the behavior of a complex system is not entirely predictable. Moreover, the dynamic nature of the systems makes for moving targets and sets limits to the degree of precision we can hope for. Understanding the patient’s context is as much precision medicine as it should be practiced by physicians as anything molecular and maybe more so. To truly appreciate the context requires heart as well as head. This is the complexity of patient care and as long as humans need care, we will need doctors. The term silver or magic bullet continues to be used today and a sense of optimism demands that we must recognize that magic comes in different forms and bullets can vary in caliber.
In the first part of this paper, I argue that what we consider to be a “mechanism,” “level,” or “component” depends on the perspectives that scientists have explicitly or implicitly adopted. If this is right, interlevel explanations and intertheoretic reductions become intimately connected. That is, I show that we cannot make sense of competing interlevel explanations of the same phenomena without reference to how those different levels of analysis relate or reduce to one another. And likewise, we cannot make sense of intertheoretic reductions (e.g., Newtonian to Relativistic equations of motion) without reference to how explanations of the same phenomena produced by those different perspectives compare. To better understand this connection between interlevel explanations and intertheoretic reductions a distinction is drawn in the second half of this paper, though only provisionally, between strong and weak relations. In the end, this distinction is removed as it only suggests ideals which are never reached in practice. Nevertheless the distinction helps us to understand how scientists can relate multiple perspectives to one another and also why they should always ultimately try to seek out newer, wider and deeper perspectives. In the end, I argue that how to relate interlevel explanations and complete theoretical reductions in science cannot be answered in the abstract by purely philosophical considerations, but only with reference to, and in accordance with, the actual history and practice of science. This is true not only for physical, but also for all empirical theories, something I show with a brief example from current cancer research.
Many different types of chemical exposures can increase the incidence of tumors in animals and humans, but usually a long period of time is required before the carcinogenic risk of an exposure is manifested. Both of these observations can be explained by a multistep/multigene model of carcinogenesis. In this model, a normal cell evolves into a cancer cell as the result of heritable changes in multiple, independent genes. The two-stage model of initiation and promotion for chemical carcinogenesis has provided a paradigm by which chemicals can act by qualitatively different mechanisms, but the process of carcinogenesis is now recognized as more complex than simply initiation and promotion. Even a three-stage model of initiation, promotion, and progression, which can be operationally defined, is not adequate to describe the carcinogenic process. The number of genes altered in a cancer cell compared to a normal cell is not known; recent evidence suggests that 3-10 genetic events are involved in common adult malignancies in humans. Two distinct classes of genes, protooncogenes and tumor-suppressor genes, are involved in the cancer process. Multiple oncogenes may be activated in a tumor, while multiple tumor-suppressor genes may be inactivated. Identification of the genes involved in carcinogenesis and elucidation of the mechanisms of their activation or inactivation allows a better understanding of how chemical carcinogens influence the process of neoplastic evolution. The findings of multiple genetic changes (including point mutations, chromosomal translocations, deletions, gene amplification, and numerical chromosome changes) in activated protooncogenes and inactivated tumor-suppressor genes provide experimental support for Boveri's somatic mutation theory of carcinogenesis. In addition to mutagenic mechanisms, chemicals may heritably alter cells by epigenetic mechanisms and enhance the clonal expansion of altered cells. Most chemical carcinogens operate via a combination of mechanisms, and even their primary mechanism of action may vary depending on the target tissues. The classification of chemicals by mechanism of action or by nongenotoxic or genotoxic activity has certain inherent difficulties because no classification of chemicals is exhaustive or definitive.
Chronic myelogenous leukemia (CML) is caused by the BCR-ABL tyrosine kinase, the product of the Philadelphia chromosome. Imatinib mesylate, formerly STI571, is a selective inhibitor of this kinase.
A total of 532 patients with late--chronic-phase CML in whom previous therapy with interferon alfa had failed were treated with 400 mg of oral imatinib daily. Patients were evaluated for cytogenetic and hematologic responses. Time to progression, survival, and toxic effects were also evaluated.
Imatinib induced major cytogenetic responses in 60 percent of the 454 patients with confirmed chronic-phase CML and complete hematologic responses in 95 percent. After a median follow-up of 18 months, CML had not progressed to the accelerated or blast phases in an estimated 89 percent of patients, and 95 percent of the patients were alive. Grade 3 or 4 nonhematologic toxic effects were infrequent, and hematologic toxic effects were manageable. Only 2 percent of patients discontinued treatment because of drug-related adverse events, and no treatment-related deaths occurred.
Imatinib induced high rates of cytogenetic and hematologic responses in patients with chronic-phase CML in whom previous interferon therapy had failed.
BRAF oncogenic mutations have been identified in significant numbers of melanocytic lesions. To correlate BRAF mutation and melanoma progression, we screened BRAF mutations in 65 melanocytic lesions, including nevi, radial growth phase (RGP), vertical growth phase (VGP) melanomas, and melanoma metastases, as well as 25 melanoma cell lines. PCR and direct sequencing were used to analyze DNA samples extracted from laser capture microdissected tissues. A similar high frequency (62-72%) of BRAF oncogenic mutations was identified in melanocytic nevi, VGP, metastatic melanomas, and melanoma cell lines [H. Davies et al., Nature (Lond.), 417: 949-954, 2002; P. M. Pollock et al., Nat. Genet., 33: 19-20, 2002; and M. S. Brose et al., Cancer Res., 62: 6997-7000, 2002]. In striking contrast, we found BRAF lesions in only 10% of the earliest stage or RGP melanomas. These findings imply that BRAF mutations cannot be involved in the initiation of the great majority of melanomas but instead reflect a progression event with important prognostic implications in the transition from the great majority of RGP melanomas to VGP and/or metastatic melanoma.
We have used nuclear transplantation to test whether the reprogramming activity of oocytes can reestablish developmental pluripotency of malignant cancer cells. We show here that the nuclei of leukemia, lymphoma, and breast cancer cells could support normal preimplantation development to the blastocyst stage but failed to produce embryonic stem (ES) cells. However, a blastocyst cloned from a RAS-inducible melanoma nucleus gave rise to ES cells with the potential to differentiate into multiple cell types in vivo including melanocytes, lymphocytes, and fibroblasts. Chimeras produced from these ES cells developed cancer with higher penetrance, shorter latency, and an expanded tumor spectrum when compared with the donor mouse model. These results demonstrate that the secondary changes of a melanoma nucleus are compatible with a broad developmental potential but predispose mice to melanomas and other malignant tumors on reactivation of RAS. Our findings serve as a paradigm for studying the tumorigenic effect of a given cancer genome in the context of a whole animal.
Genetic instability has long been hypothesized to be a cardinal feature of cancer. Recent work has strengthened the proposal that mutational alterations conferring instability occur early during tumour formation. The ensuing genetic instability drives tumour progression by generating mutations in oncogenes and tumour-suppressor genes. These mutant genes provide cancer cells with a selective growth advantage, thereby leading to the clonal outgrowth of a tumour. Here, we discuss the role of genetic instability in tumour formation and outline future work necessary to substantiate the genetic instability hypothesis.
Malignant mouse teratocarcinoma (or embryonal carcinoma) cells with a normal modal chromosome number were taken from the "cores" of embryoid bodies grown only in vivo as an ascites tumor for 8 years, and were injected into blastocysts bearing many genetic markers, in order to test the developmental capacities, genetic constitution, and reversibility of malignancy of the core cells. Ninety-three live normal pre- and postnatal animals were obtained. Of 14 thus far analyzed, three were cellular genetic mosaics with substantial contributions of tumor-derived cells in many developmentally unrelated tissues, including some never seen in the solid tumors that form in transplant hosts. The tissues functioned normally and synthesized their specific products (e.g., immunoglobulins, adult hemoglobin, liver proteins) coded for by strain-type alleles at known loci. In addition, a tumor-contributed color gene, steel, not previously known to be present in the carcinoma cells, was detected from the coat phenotype. Cells derived from the carcinoma, which is of X/Y sex chromosome constitution, also contributed to the germ line and formed reproductively functional sperms, some of which transmitted the steel gene to the progeny. Thus, after almost 200 transplant generations as a highly malignant tumor, embryoid body core cells appear to be developmentally totipotent and able to express, in an orderly sequence in differentiation of somatic and germ-line tissues, many genes hitherto silent in the tumor of origin. This experimental system of "cycling" teratocarcinoma core cells through mice, in conjunction with experimental mutagenesis of those cells, may therefore provide a new and useful tool for biochemical, developmental, and genetic analyses of mammalian differentiation. The results also furnish an unequivocal example in animals of a non-mutational basis for transformation to malignancy and of reversal to normalcy. The origin of this tumor from a disorganized embryo suggests that malignancies of some other, more specialized, stem cells might arise comparably through tissue disorganization, leading to developmental aberrations of gene expression rather than changes in gene structure.
A definitive test for developmental totipotency of mouse malignant teratocarcinoma cells was conducted by cloning singly injected cells in genetically marked blastocysts. Totipotency was conclusively shown in an adult mosaic female whose tumor-strain cells had made substantial contributions to all of the wide range of its somatic tissues analyzed; the clonally propagated cell lineage had therefore differentiated in numerous normal directions. The test cells were from "cores" of embryoid bodies of a euploid, chromosomally male (X/Y), ascites tumor grown only in vivo by transplantation for 8 years. The capacity of cells from the same source to differentiate, in a phenotypic male, into reproductively functional sperms, has been shown in our previous experiments [(1975) Proc. Nat. Acad. Sci. USA 72, 3585-3589]. Cells from this transplant line therefore provide material suitable for projected somatic and germ-line genetic analyses of mammalian differentiation based on "cycling" of mutation-carrying tumor cells through developing embryos. In some animals obtained from single-cell injections tumor-derived cells were sporadically distributed in developmentally unrelated tissues. These cases can be accounted for by delayed and haphazard cellular integration, and by a marked degree of sustained cellular developmental flexibility in early mammalian development, irrespective of certain classical "germ-layer" designations. All mosaic mice obtained have thus far been free of teratomas. In one case, the injected stem cell contributed only to the pancreas and gave rise to a malignancy resembling pancreatic adenocarcinoma. The high modal frequency of euploidy in these individually tested cells thus tends to indicate that a near-normal chromosome complement is sufficient for total restoration of orderly gene expression in a normal embryonic environment; it may also be necessary for teratoma stem-cell proliferation to be terminated there.
The E6 protein encoded by the oncogenic human papillomavirus types 16 and 18 is one of two viral products expressed in HPV-associated cancers. E6 is an oncoprotein which cooperates with E7 to immortalize primary human keratinocytes. Insight into the mechanism by which E6 functions in oncogenesis is provided by the observation that the E6 protein encoded by HPV-16 and HPV-18 can complex the wild-type p53 protein in vitro. Wild-type p53 gene has tumor suppressor properties, and is a target for several of the oncoproteins encoded by DNA tumor viruses. In this study we demonstrate that the E6 proteins of the oncogenic HPVs that bind p53 stimulate the degradation of p53. The E6-promoted degradation of p53 is ATP dependent and involves the ubiquitin-dependent protease system. Selective degradation of cellular proteins such as p53 with negative regulatory functions provides a novel mechanism of action for dominant-acting oncoproteins.
The putative oncogene bcl-2 is juxtaposed to the immunoglobulin heavy chain (Igh) locus by the t(14;18) chromosomal translocation typical of human follicular B-cell lymphomas. The bcl-2 gene product is not altered by the translocation, but its expression is deregulated, presumably by the Igh enhancer E mu. Constitutive bcl-2 expression seems to augment cell survival, as infection with a bcl-2 retrovirus enables certain growth factor-dependent mouse cell lines to maintain viability when deprived of factor. Furthermore, high levels of the bcl-2 product can protect human B and T lymphoblasts under stress and thereby confer a growth advantage. Mice expressing a bcl-2 transgene controlled by the Igh enhancer accumulate small non-cycling B cells which survive unusually well in vitro but do not show a propensity for spontaneous tumorigenesis. In contrast, an analogous myc transgene, designed to mimic the myc-Igh translocation product typical of Burkitt's lymphoma and rodent plasmacytoma, promotes B lymphoid cell proliferation and predisposes mice to malignancy in pre-B and B lymphoid cells. Previous experiments have suggested that bcl-2 can cooperate with deregulated myc to improve in vitro growth of pre-B and B cells. Here we describe a marked synergy between bcl-2 and myc in doubly transgenic mice. E mu-bcl-2/myc mice show hyperproliferation of pre-B and B cells and develop tumours much faster than E mu-myc mice. Suprisingly, the tumours derive from a cell with the hallmarks of a primitive haemopoietic cell, perhaps a lymphoid-committed stem cell.
We have analyzed the molecular genetics of the breakpoints involved in the t(8;14) and t(14;18) translocations of an acute pre-B-cell leukemia from a patient with a history of follicular lymphoma. In this patient's leukemic cells, the breakpoint of the t(14;18) translocation occurred in the major breakpoint-cluster region of the BCL2 gene and became linked to the JH4 joining-region gene segment of the immunoglobulin heavy-chain locus on the 14q+ chromosome as previously observed in follicular lymphoma. An N region and heptamer and nonamer signal sequences indicated that this translocation occurred as a mistake in VH-DH-JH joining (where VH and DH are the variable and diversity segments). In the t(8;14) translocation, the breakpoint was located immediately 5' of the first exon of the MYC protooncogene, which was juxtaposed with the C gamma 2 constant gene segment of the second 14q+ chromosome. The finding of repeated sequences typical of switch regions suggested that this translocation occurred during heavy-chain isotype switching, resulting in progression to pre-B-cell leukemia with both the t(8;14) and the t(14;18) translocations. The terminal deoxynucleotidyltransferase-positive phenotype of the patient's leukemic cells further suggests that the pre-B-cell leukemia was derived from a pre-B cell carrying a t(14;18) translocation in the original follicular lymphoma. The polymerase chain reaction method was then used to identify cancer cells in the bone marrow of the patient.
A common feature of follicular lymphoma, the most prevalent haematological malignancy in humans, is a chromosome translocation (t(14;18] that has coupled the immunoglobulin heavy chain locus to a chromosome 18 gene denoted bcl-2. By analogy with the translocated c-myc oncogene in other B-lymphoid tumours bcl-2 is a candidate oncogene, but no biological effects of bcl-2 have yet been reported. To test whether bcl-2 influences the growth of haematopoietic cells, either alone or together with a deregulated c-myc gene, we have introduced a human bcl-2 complementary DNA using a retroviral vector into bone marrow cells from either normal or E mu-myc transgenic mice, in which B-lineage cells constitutively express the c-myc gene. Bcl-2 cooperated with c-myc to promote proliferation of B-cell precursors, some of which became tumorigenic. To determine how bcl-2 expression impinges on growth factor requirements, the gene was introduced into a lymphoid and a myeloid cell line that require interleukin 3 (IL-3). In the absence of IL-3, bcl-2 promoted the survival of the infected cells but they persisted in a G0 state, rather than proliferating. These results argue that bcl-2 provided a distinct survival signal to the cell and may contribute to neoplasia by allowing a clone to persist until other oncogenes, such as c-myc, become activated.
Transgenic mice bearing the cellular myc oncogene coupled to the immunoglobulin mu or kappa enhancer frequently develop a fatal lymphoma within a few months of birth. Since the tumours represent represent both immature and mature B lymphocytes, constitutive c-myc expression appears to be highly leukaemogenic at several stages of B-cell maturation. These myc mice should aid study of lymphoma development, B-cell ontogeny and immunoglobulin regulation.
The 15;12 chromosome translocation in murine plasmacytomas and the 8;14 in human Burkitt lymphomas often link the cellular myc oncogene to the locus for constant regions of immunoglobulin heavy chains (CH locus). To clarify how and why c-myc translocation occurs, we have sequenced the mouse and human c-myc genes and correlated c-myc transcription with c-myc rearrangement. Both genes comprise three exons; the second and third encode the myc polypeptide, which is conserved between mammals and birds, particularly in its more basic C-terminal half. Southern blots showed that four of 12 Burkitt lines have c-myc linked near CH switch regions and two near the joining region (JH) locus. Hence, immunoglobulin recombination machinery may participate in translocation, although the common myc breakpoint region around exon 1 does not resemble a switch region. Tumours with breakpoints just 5' to exon 1, or distant from c-myc, had normal c-myc mRNAs of 2.25 and 2.4 kb, which differ at their 5' ends, while tumours with breakpoints within exon 1 or intron 1 had altered c-myc mRNAs (2.1-2.7 kb in Burkitt lines), initiated within intron 1. Both types of mRNAs probably yield the same polypeptide. Since the untranslocated c-myc allele was generally silent, translocation to the CH locus must induce constitutive c-myc expression. The presence of c-myc mRNA in immortal but non-tumorigenic lymphoblastoid cell lines may implicate c-myc in an immortalization step.
Three criteria have been used to identify cellular genes that might play a role in oncogenesis: (i) homology with known viral transforming genes (v-onc's); (ii) activated expression in tumor cells; and (iii) transforming activity in cultured mouse cells. We have been exploring the hypothesis that retroviruses lacking oncogenes activate cellular oncogenes by insertional mutagenesis. Our approach is to locate proviruses within the chromosomal DNA of clonal populations of tumor cells, and to identify activated transcriptions of tumor cells, and to identify activated transcriptional units in flanking cellular DNA. The central findings that have emerged from such studies in our laboratory and others indicate that: (i) insertion of avian leukosis virus (ALV) DNA can activate c-myc, a previously identified cellular homologue of a viral transforming gene, by various arrangements of proviral and c-myc DNA; (ii) most mammary carcinomas in C3H mice carry new mouse mammary tumor virus (MMTV) proviruses within an unidentified 20 kilobase region of the mouse genome that contains at least one activated transcriptional unit; (iii) proviruses of three viruses (ALV), chicken syncytial virus (CSV), and myeloblastosis-associated virus (MAV) are present in the c-myc locus in avian B cell lymphomas, suggesting that the same gene is activated during induction of a single type of tumor by different viruses; and (iv) MAV-induced nephroblastomas do not contain proviral insertions near c-myc, implying that the same virus may affect different genes in different types of tumor.
Epstein-Barr virus, a human herpesvirus that persists within the B-lymphoid system, can enhance the survival potential of latently infected B cells in vitro through up-regulation of the cellular survival protein Bcl-2. The possibility that an analogous effect is operative in lytically infected cells was suggested by the observation of distant sequence homology between an Epstein-Barr virus-coded early lytic cycle protein, BHRF1, and Bcl-2. Here we show by gene transfer that BHRF1 resembles Bcl-2 both in its subcellular localization and in its capacity to enhance B-cell survival. Thus confocal microscopic analysis of cells acutely cotransfected with BHRF1 and Bcl-2 expression vectors revealed substantial colocalization of the two proteins in the cytoplasm. In subsequent experiments, stable BHRF1 gene transfectants of Burkitt lymphoma cells paralleled Bcl-2 transfectants in their enhanced survival under conditions that induce cell death by apoptosis. Despite their limited sequence conservation, therefore, the two proteins appear to be functionally homologous. We suggest that BHRF1 provides an alternative, Bcl-2-independent, means of enhancing B-cell survival that may operate during the virus lytic cycle.
Cigarette smoke carcinogens such as benzo[a]pyrene are implicated in the development of lung cancer. The distribution of benzo[a]pyrene diol epoxide (BPDE) adducts along exons of the P53 gene in BPDE-treated HeLa cells and bronchial epithelial cells was mapped at nucleotide resolution. Strong and selective adduct formation occurred at guanine positions in codons 157, 248, and 273. These same positions are the major mutational hotspots in human lung cancers. Thus, targeted adduct formation rather than phenotypic selection appears to shape the P53 mutational spectrum in lung cancer. These results provide a direct etiological link between a defined chemical carcinogen and human cancer.
We wish to thank Terry Schoop of Biomed Arts Associates, San Francisco, for preparation of the figures, Cori Bargmann and Zena Werb for insightful comments on the manuscript, and Normita Santore for editorial assistance. In addition, we are indebted to Joe Harford and Richard Klausner, who allowed us to adapt and expand their depiction of the cell signaling network, and we appreciate suggestions on signaling pathways from Randy Watnick, Brian Elenbas, Bill Lundberg, Dave Morgan, and Henry Bourne. R. A. W. is a Ludwig Foundation and American Cancer Society Professor of Biology. His work has been supported by the Department of the Army and the National Institutes of Health. D. H. acknowledges the support and encouragement of the National Cancer Institute. Editorial policy has rendered the citations illustrative but not comprehensive.
Most cancers have many chromosomal abnormalities, both in number and in structure, whereas some show only a single aberration. In the era before molecular biology, cancer researchers, studying both human and animal cancers, proposed that a small number of events was needed for carcinogenesis. Evidence from the recent molecular era also indicates that cancers can arise from small numbers of events that affect common cell birth and death processes.
Resistance to the ABL kinase inhibitor imatinib (STI571 or Gleevec) in chronic myeloid leukemia (CML) occurs through selection for tumor cells harboring BCR-ABL kinase domain point mutations that interfere with drug binding. Crystallographic studies predict that most imatinib-resistant mutants should remain sensitive to inhibitors that bind ABL with less stringent conformational requirements. BMS-354825 is an orally bioavailable ABL kinase inhibitor with two-log increased potency relative to imatinib that retains activity against 14 of 15 imatinib-resistant BCR-ABL mutants. BMS-354825 prolongs survival of mice with BCR-ABL-driven disease and inhibits proliferation of BCR-ABL-positive bone marrow progenitor cells from patients with imatinib-sensitive and imatinib-resistant CML. These data illustrate how molecular insight into kinase inhibitor resistance can guide the design of second-generation targeted therapies.
Differentiated cells can be reprogrammed to an embryonic-like state by transfer of nuclear contents into oocytes or by fusion with embryonic stem (ES) cells. Little is known about factors that induce this reprogramming. Here, we demonstrate induction of pluripotent stem cells from mouse embryonic or adult fibroblasts by introducing four factors, Oct3/4, Sox2, c-Myc, and Klf4, under ES cell culture conditions. Unexpectedly, Nanog was dispensable. These cells, which we designated iPS (induced pluripotent stem) cells, exhibit the morphology and growth properties of ES cells and express ES cell marker genes. Subcutaneous transplantation of iPS cells into nude mice resulted in tumors containing a variety of tissues from all three germ layers. Following injection into blastocysts, iPS cells contributed to mouse embryonic development. These data demonstrate that pluripotent stem cells can be directly generated from fibroblast cultures by the addition of only a few defined factors.
Although restoration of p53 function is an attractive tumor-specific therapeutic strategy, it remains unclear whether p53 loss is required only for transition through early bottlenecks in tumorigenesis or also for maintenance of established tumors. To explore the efficacy of p53 reinstatement as a tumor therapy, we used a reversibly switchable p53 knockin (KI) mouse model that permits modulation of p53 status from wild-type to knockout, at will. Using the well-characterized Emu-myc lymphoma model, we show that p53 is spontaneously activated when restored in established Emu-myc lymphomas in vivo, triggering rapid apoptosis and conferring a significant increase in survival. Nonetheless, reimposition of p53 function potently selects for emergence of p53-resistant tumors through inactivation of p19(ARF) or p53. Our study provides important insights into the nature and timing of p53-activating signals in established tumors and how resistance to p53 evolves, which will aid in the optimization of p53-based tumor therapies.
Aberrant gene function and altered patterns of gene expression are key features of cancer. Growing evidence shows that acquired epigenetic abnormalities participate with genetic alterations to cause this dysregulation. Here, we review recent advances in understanding how epigenetic alterations participate in the earliest stages of neoplasia, including stem/precursor cell contributions, and discuss the growing implications of these advances for strategies to control cancer.
Most, if not all, cancers are composed of cells in which more than one gene has a cancer-promoting mutation. Although recent evidence has shown the benefits of therapies targeting a single mutant protein, little attention has been given to situations in which experimental tumors are induced by multiple cooperating oncogenes. Using combinations of doxycycline-inducible and constitutive Myc and mutant Kras transgenes expressed in mouse mammary glands, we show that tumors induced by the cooperative actions of two oncogenes remain dependent on the activity of a single oncogene. Deinduction of either oncogene individually, or both oncogenes simultaneously, led to partial or complete tumor regression. Prolonged remission followed deinduction of Kras G12D in the context of continued Myc expression, deinduction of a MYC transgene with continued expression of mutant Kras produced modest effects on life extension, whereas simultaneous deinduction of both MYC and Kras G12D transgenes further improved survival. Disease relapse after deinduction of both oncogenes was associated with reactivation of both oncogenic transgenes in all recurrent tumors, often in conjunction with secondary somatic mutations in the tetracycline transactivator transgene, MMTV-rtTA, rendering gene expression doxycycline-independent. These results demonstrate that tumor viability is maintained by each gene in a combination of oncogenes and that targeted approaches will also benefit from combination therapies.
• inducible
• mammary gland
• ras
Preferential formation of benzo
- Denissenko
BRAF oncogenic mutations correlate with progression rather than initiation of human melanoma
- Dong J
Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia
- Kantarjian
Epstein-Barr virus coded bhrf1 protein, a viral homolog of bcl 2, protects human b cells from programmed cell death
- Henderson
Genetic instability and Darwinian selection in tumours
- Cahill