Somatic Mutation Theory Of Carcinogenesis Research Articles

Cell Reversal From a Differentiated to a Stem-Like State at Cancer Initiation.

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.

An Integrative Approach Toward Biology, Organisms, and Cancer.

Over the last two decades, we have challenged the hegemony of the somatic mutation theory of carcinogenesis (SMT) based on the lack of theoretical coherence of the premises adopted by its followers. We offered instead a theoretical alternative, the tissue organization field theory (TOFT), that is based on the premises that cancer is a tissue-based disease and that proliferation and motility is the default state of all cells. We went on to use a theory-neutral experimental protocol that simultaneously tested the TOFT and the SMT. The results of this test favored adopting the TOFT and rejecting the SMT. Recently, an analysis of the differences between the Physics of the inanimate and that of the living matter has led us to propose principles for the construction of a much needed theory of organisms. The three biological principles are (a) a default state, (b) a principle of variation, and (c) one of organization. The TOFT, defined as "development gone awry," fits well within the principles that we propose for a theory of organisms. This radical conceptual change opened up the possibility of anchoring mathematical modeling on genuine biological principles. By identifying constraints to the default state, multilevel biomechanical explanations become as legitimate as the molecular ones on which other modelers that adopt the SMT rely. Expanding research based on the premises of our theory of organisms will enrich a comprehensive understanding of normal development and of the one that goes awry.

Radiation, Cancer, and Mutation in the Atomic Age

Following World War II, the publication of accounts such as John Hersey’s Hiroshima (1946) documented the devastating effects of atomic weaponry on inhabitants of the two Japanese cities targeted by atomic bombs. Yet the American government presented a positive image of the atom’s benefits for its citizens in peacetime. In the late 1940s and 1950s, the U.S. Atomic Energy Commission sought to develop nuclear medicine and nuclear energy alongside its continued production and testing of atomic weapons. In both its civilian and military endeavors, the agency maintained that its safety guidelines were sufficient to protect workers and the general population from dangerous exposures to ionizing radiation. In the 1950s, mounting concerns about the hazards of low-level radiation exposure, particularly from atomic weapons fallout, raised the stakes of understanding and protecting against the health hazards of ionizing radiation. Radiological protection guidelines focused on preventing the somatic effects of radiation—leukemia, cancer, and life-shortening—for which experts postulated a safety threshold. By contrast, the genetic effects of ionizing radiation on an individual’s fertility and gametes appeared to be dose-dependent even at the lowest levels. Geneticists challenged the perceived gap between somatic and genetic effects of radiation by arguing that radiation-induced mutations play a role in diseases, especially cancer. In doing so, they also contested the Commission’s portrayal of a safe atomic future. This article examines how concerns over low-level radiation from fallout facilitated acceptance of the then-controversial somatic mutation theory of carcinogenesis, which became an enduring feature of cancer biology.

Tumor and the microenvironment: a chance to reframe the paradigm of carcinogenesis?

The somatic mutation theory of carcinogenesis has eventually accumulated an impressive body of shortfalls and paradoxes, as admittedly claimed by its own supporters given that the cell-based approach can hardly explain the emergence of tissue-based processes, like cancer. However, experimental data and alternatives theories developed during the last decades may actually provide a new framework on which cancer research should be reframed. Such issue may be fulfilled embracing new theoretical perspectives, taking the cells-microenvironment interplay as the privileged level of observation and assuming radically different premises as well as new methodological frameworks. Within that perspective, the tumor microenvironment cannot be merely considered akin to new “factor” to be added to an already long list of “signaling factors”; microenvironment represents the physical-biochemical support of the morphogenetic field which drives epithelial cells towards differentiation and phenotype transformation, according to rules understandable only by means of a systems biology approach. That endeavour entails three fundamental aspects: general biological premises, the level of observation (i.e., the systems to which we are looking for), and the principles of biological organization that would help in integrating and understanding experimental data.

One hundred years of somatic mutation theory of carcinogenesis: Is it time to switch?

During this current year of 2014 biologists and cancer researchers will commemorate the centenary of the publication of Zur Frage der Entstehung maligner Tumoren (On the Origin of Malignant Tumors, Williams & Wilkins. Philadelphia, PA, USA) by the German zoologist Theodor Boveri, a book that directly and indirectly impacted both the biological sciences at large and cancer research in particular. Before 1914, Boveri made important contributions in the fields of Mendelian inheritance, cellular and developmental biology: among others, the Sutton– Boveri theory of chromosomal inheritance; the individuality of chromosomes and the concept that the assortment of chromosomes rather than their number was necessary for development; the finding that comparable sets of chromosomes are contributed by the oocyte and the sperm. Boveri also paved the way for the discovery of the “organizer” by Spemann and Mangold [1]. These contributions were the fruit of his great observational skills, experimental ingenuity and dexterity, and his theorizing acuity. Finally, he wrote the aforementioned book, widely acknowledged to be seminal in cancer pathogenesis.

Tumours and tissues: similar homeostatic systems?

The currently prevalent somatic mutation theory of carcinogenesis and metastases explicitly assumes that cancer is a cellular disease, i.e. a disease of the control of cell proliferation and/or cell differentiation. Accordingly, explanations should always be sought for at a gene and/or gene product level, regardless of the level of organization at which the phenomenon is observed. Such a reductionist approach characterized the century-old effort to find cancer cell singularities, absent in normal cells, without apparent success, however. More recently alternative views have been put forward, assuming that cancer is a tissue-based disease involving disturbed interactions within the tissue architecture. In this review, selected reports on normal tissue homeostasis and bone marrow contribution to both tumour cells and tumour stroma are reviewed. Regarding normal tissues, the existence of a complex homeostatic system actually involving the whole organism emerges. Regarding tumours, remarkable similarities with normal tissue activities are apparent, providing some evidence that tumours share many biological features and processes with normal tissues. The review supports the concept that cancer is a tissue-based disease and that its pathological nature may result from unbalanced/untimely activation of otherwise normal physiological processes.

Molecular mechanism of the “feedback loop” model of carcinogenesis

It is commonly accepted that cancer is a genetic disease. The current prevailing theory of carcinogenesis is the somatic mutation theory of carcinogenesis and metastasis (SMT). This theory postulates that mutations in epithelial cells lead to uncontrolled proliferation of tumor cells in a cell-autonomous fashion. This cell-autonomy is increasingly criticized. Current data suggest that the tumor microenvironment is also strongly involved in carcinogenesis. Recently, we published a hypothesis that considers the important contribution of the tumor microenvironment in carcinogenesis and complements the classical clonal evolution model.Essentially, this “feedback loop model” (FBM) postulates that the physiological communication between cancer cells and stromal cells in inflammatory or proliferative conditions is altered by anomalous signal processing within the parenchymal cells. The inability of parenchymal cells to correctly finalize the intercellular communication might result in a perpetuation of the activated state of cells and the tumor micromilieu. The FBM is unique among the tissue-based models because in this model tumor and stromal cells interact together in a reciprocal manner to form the cancer phenotype. Contrary to the SMT, the FBM postulates that mutated genes act in a cell-heteronomous fashion, not in a cell-autonomously fashion.

Das „feedback loop model“ – ein neues hypothetisches Modell zur frühen Karzinogenese

The classical somatic mutation theory of carcinogenesis and metastases (SMT) explains malignant transformation by incidence of mutations in oncogenes or tumor suppressor genes. These mutations lead to a cell-autonomous activation and thereby growth advantage compared to neighbouring cells. However, this SMT does not seem fit to completely explain many characteristics of carcinomas. Contrary to the cell centered view on carcinogenesis of the SMT, research recently showed more and more evidence that the tumor microenvironment is involved in carcinogenesis, too.

Human tumour clonality assessment—flawed but necessary

One of the premises of the somatic mutation theory of carcinogenesis is that tumours are clonal lesions derived from a single mutated stem cell progenitor. This theory spawned a proliferation of clonality studies, using a variety of different molecular markers to try to determine tumour clonality in multiple organs. In order to establish true clonality, it is necessary to identify the original founding mutation that occurred at the initiation of the progenitor clone. Use of other lesions may only serve to identify sub-clones. As founding mutations have not been properly established in many organ systems, human clonality assessments carry this caveat. However it is only through clonality and mutation burden assessments that phylogenetic tress become established. Here, we review the advantages, disadvantages and use of different clonality markers.

Glycophorin-A Mutations as a Window to Study Carcinogenesis

For risk assessment, it is necessary to evaluate the dose of human exposure to mutagens. Previous studies support the somatic mutation theory of carcinogenesis. It is therefore of great importance ...

Somatic mutation theory of carcinogenesis: why it should be dropped and replaced.

The somatic mutation theory of carcinogenesis has been the dominant force driving cancer research during the 20th century. In brief, it proposes that successive DNA mutations in a single cell cause cancer (monoclonality). This theory places carcinogenesis at the cellular and subcellular hierarchical levels of biological complexity. Its basic premises are that (1) cancer is a defect of the control of cell proliferation and (2) the default state of metazoan cells is quiescence. These two premises have recently been contradicted by evidence. Supporters of the theory have dealt with these lacks of fit by incorporating ad hoc explanations similar to the use of epicycles in pre-Copernican astronomy. We propose the adoption of an alternative theory, the tissue organization field theory of carcinogenesis and neoplasia. Its basic premises are that (1) proliferation is the default state of all cells and (2) carcinogenesis and neoplasia are defects of tissue architecture. Carcinogens would act initially by disrupting the normal interactions that take place among cells in the parenchyma and stroma of an organ (the equivalent of the "morphogenetic fields" of developing organisms). Stroma appears as the primary target of carcinogens. Carcinogenesis and neoplasia occur entirely through emergent (supracellular) phenomena. Neoplastic cells may be reprogrammed to behave like "normal" cells within normal tissues. We argue that it is necessary to abandon the somatic mutation theory. Researchers will then become free to adopt alternative reliable premises to build a theory that explains carcinogenesis as another outcome, aberrant as it may be, of biological organization.

Somatic-cell mutations as a possible predictor of cancer risk.

The somatic-mutation theory of carcinogenesis has received strong scientific support from results of recent studies on tumor-suppressor genes. We anticipated that people among the high risk for cancer group, either through exposure to various ionizing radiations or by virtue of unique genotypes, would also manifest increased frequencies of somatic mutation. This report presents the results of two somatic-mutation assays--at the erythrocyte glycophorin A (GPA) and lymphocyte T-cell receptor (TCR) genes--in various groups at high risk for cancer development, including atomic-bomb survivors, patients with various cancers, patients administered Thorotrast, and patients with genetic disorders that make them cancer prone. Although neither the GPA-mutation nor the TCR-mutation assay detects gene mutations directly related to carcinogenesis, increased mutation frequencies were detected by both assays in many individuals among the high-risk groups and among cancer patients. We have continued to follow up those individuals who show values of about three times higher than those of the control group. Thus, these assays may prove useful for identifying high-risk cancer groups and for estimating the effects of mutagens. Such information would constitute a valuable data base for epidemiological studies.

Mechanisms of multistep carcinogenesis and carcinogen risk assessment.

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.

Mutagen is a mutagen, not necessarily a carcinogen.

A largely unspoken but underlying assumption that has been made by authors throughout these proceedings is that processes involved in antimutagenesis are related to anticarcinogenesis, a corollary of the somatic mutation theory of carcinogenesis. It is generally known that most carcinogens are mutagens, but certainly not all chemicals that are mutagenic in short-term in vitro mutagenicity tests are carcinogens. Reasons that contribute to this lack of concordance are discussed later.

Role of aneuploidy in early and late stages of neoplastic progression of Syrian hamster embryo cells in culture.

There is increasing evidence in support of the somatic mutation theory of carcinogenesis (2,6,8,12–15,21,36,49,50,56,57,60,70). The recent demonstrations of the involvement of point mutations in the activation of the ras oncogenes (49,60), the associations of chromosomal rearrangements with proto-oncogenes (50,70), and the amplification of oncogenes (36,56,57) in certain tumors add to other lines of evidence, such as the demonstration of DNA as a critical target in neoplastic transformation (6,8) and the correlation between mutagenesis and carcinogenesis (2,8,12,13) with most chemicals (see Ref. 8, 41, and 51 for discussion of the arguments against the somatic mutation theory).

Mutational approaches to the study of carcinogenesis

A number of circumstantial lines of evidence are consistent with the somatic mutation theory of carcinogenesis, but there has been a paucity of experimental data that either support or contradict the genetic theory. In this paper, we summarize the predictions, the recent experimental approaches, and the problems involved in testing the theory. Results are presented that define the conditions and demonstrate the existence of two-stage processes of mutagenesis and carcinogenesis in vitro. We conclude that mutagenesis is responsible for the initiation of carcinogenesis and an epigenetic mechanism is responsible for its promotion. Carcinogenic agents can induce a stable transformation of a cell by either mutation or epigenetic alteration in gene expression. This conclusion has led us to propose a new integrative theory of carcinogenesis, encompassing the tenets of four main theories: (1) the mutation and epigenetic basis for carcinogenesis, (2) the two-stage theory of carcinogenesis, (3) a general theory of carcinogenesis, and (4) the somatic deletion mutation theory of carcinogenesis.

Mutagenicity of epoxides of polycyclic hydrocarbons correlates with carcinogenicity of parent hydrocarbons.

MANY chemical carcinogens are mutagenic1 and some non-mutagenic carcinogens are metabolized to mutagenic derivatives2,3. Recent work4–6 has confirmed that epoxides are intermediates in the metabolism of the aromatic double bonds of carcinogenic polycyclic hydrocarbons to hydroxylated derivatives, as Boyland suggested7. In addition to chemical reactions with nucleic acids and histone8, epoxides derived from polycyclic hydrocarbons bind more extensively to the nucleic acids of cells in culture than the parent hydrocarbons9. Hydrocarbon epoxides are also more active in inducing malignant transformation in vitro of hamster embryo and mouse prostate cells10 although, in whole animals, they were less potent carcinogens than the hydrocarbons themselves11–13. As potential mutagens, polycyclic hydrocarbon epoxides are therefore of particular interest, mainly because of the support positive results would give to the somatic mutation theory of carcinogenesis. In the work described here we have tested K-region epoxides of hydrocarbons for their ability to cause host range mutations of T2h+ bacteriophage, specifically because there is no possibility, in this test system, of the epoxides being further metabolized. The epoxides tested were phenanthrene 9,10-oxide (Ph-E), benz(a)anthracene 5,6-oxide (BA-E), dibenz(a,h)anthracene 5,6-oxide (DBA-E), 7-methylbenz(a)anthracene 5,6-oxide (7-MeBA-E), 3-methylcholanthrene 11,12-oxide (MCA-E) and chrysene 5,6-oxide (Ch-E). Ethylene oxide and propylene oxide were used as examples of aliphatic epoxides which do not increase the frequency of host range mutants of T2 bacteriophage and ethyl methanesulphonate (EMS) was used as a known mutagen14.

Multiple-mutation theory of carcinogenesis.

NEW life was given to the somatic mutation theory of carcinogenesis when it was recognized that not just one, but several mutations were probably required. Fisher and Hollomon1 thought that a number of similar mutations in adjacent cells might initiate cancer, and deduced a law of the form ( age ) p – 1 for the rate of appearance of cancers in a population, with p being the number of cells in the critical size group. They arrived at a value of p near 7 from the mortality data. Muller2 and Nordling3 thought that a number of successive mutations in the same cell might initiate cancer, and deduced a law of the same form, ( age ) p – 1 , for the rate of appearance of cancers, with p ≈ 7 now being the number of mutations required in a single cell.