SMT and TOFT: Why and How They are Opposite and Incompatible Paradigms

Bizzarri, Mariano; Cucina, Alessandra

doi:10.1007/s10441-016-9281-4

Cited by 26 publications

(16 citation statements)

References 124 publications

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“…A competing perspective is that of cancer as a circuit disease-a disorder of the complex biophysical, transcriptional, and epigenetic dynamics that regulate cellular state and the ability of cells to cooperate in vivo [6][7][8]. Under this view (sometimes called the tissue organization field theory or TOFT, [9,10]), cancer is akin to a traffic jam [11]-the problem is not a permanent discrete alteration within a founder cell and all of its clonal descendants, but an undesirable stable attractor in the complex network of controls that normally guides anatomical homeostasis [12].The relative merits of the two models have been discussed extensively [10,[13][14][15][16][17] …”

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confidence: 99%

Cancer as a disorder of patterning information: computational and biophysical perspectives on the cancer problem

Moore

Walker

Levin

2017

Converg. Sci. Phys. Oncol.

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TOPICAL REVIEWCancer as a disorder of patterning information: computational and biophysical perspectives on the cancer problem IntroductionCancer is well-recognized not only as an extremely pernicious medical problem, but also as a group of phenomena deeply connected to the fundamental questions of evolution, multicellularity, pattern (disregulation, and the interplay between the genome and the environment [1,2]. Two fundamental paradigms currently divide the field. One is that cancer results from disorders of genetics: cancer cells are fundamentally broken due to genomic mutation or instability, and their clonal progeny form tumors and metastases. This view is sometimes called the SMT, somatic mutation theory [3][4][5]. A competing perspective is that of cancer as a circuit disease-a disorder of the complex biophysical, transcriptional, and epigenetic dynamics that regulate cellular state and the ability of cells to cooperate in vivo [6][7][8]. Under this view (sometimes called the tissue organization field theory or TOFT, [9,10]), cancer is akin to a traffic jam [11]-the problem is not a permanent discrete alteration within a founder cell and all of its clonal descendants, but an undesirable stable attractor in the complex network of controls that normally guides anatomical homeostasis [12].The relative merits of the two models have been discussed extensively [10,[13][14][15][16][17] AbstractThe current paradigm views cancer as arising clonally from a degradation of genetic information in single cells. A complementary perspective, originating at the dawn of modern developmental biology, is that cancer is the result of a system disorder of algorithms that normally orchestrate individual cell activities toward specific anatomical structures and away from tumorigenesis. A view of cancer as a disease of geometry focuses on the pathways that allow cells to cooperate to build and maintain large-scale anatomical patterning. Cancer may result when cells stop maintaining higher-order structures and reduce the boundary of their computational selves to a single-cell level, reverting to a unicellular lifestyle in which the rest of the organism is merely part of the environment at the expense of which all living things survive. While this view has been widely discussed, little progress has been made in providing a quantitative, mechanistic framework within which this perspective's specific and unique implications for treatment strategies can be tested and biomedically exploited. Here, we highlight two recent areas of progress which may facilitate much-needed progress on the cancer problem. First, we review the roles that endogenous bioelectrical networks, operating across many tissues in vivo, play as a medium of information processing in tumor suppression, progression, and reprogramming. Second, we provide a primer to the development of computational theory and tools for quantifying the information and causal control structures in cancer and other complex biological systems. Rigorous mathematical formalisms now exist to...

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confidence: 99%

Cancer as a disorder of patterning information: computational and biophysical perspectives on the cancer problem

Moore

Walker

Levin

2017

Converg. Sci. Phys. Oncol.

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“…These advances "hold promise for precision medicine, 21 It may be objected that SMT and TOFT, despite their diversity, are not genuine rival theories, because they are not really incompatible. This issue is in fact strongly debated (see Bedessem, Ruphy 2017Bizzarri, Cucina 2016;Bertolaso 2016;Rosenfeld 2013). However, this issue does not impinge on our argumentation.…”

Section: Personalized Cancer Medicine 22mentioning

confidence: 81%

“…And, in fact, many of the participants in the SMT vs. TOFT debate do see those theories as really incompatible. For example, Bizzarri and Cucina (2016) state that SMT and TOFT are irreconcilable theories. According to them, "irreconcilability depends on radical divergence existing among basic premises […].…”

Section: Personalized Cancer Medicine 22mentioning

confidence: 99%

Evidence amalgamation, plausibility, and cancer research

Bertolaso

Sterpetti

2017

Synthese

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Cancer research is experiencing 'paradigm instability', since there are two rival theories of carcinogenesis which confront themselves, namely the Somatic Mutation Theory and the Tissue Organization Field Theory. Despite this theoretical uncertainty, a huge quantity of data is available thanks to the improvement of genome sequencing techniques. Some authors think that the development of new statistical tools will be able to overcome the lack of a shared theoretical perspective on cancer by amalgamating as many data as possible. We think instead that a deeper understanding of cancer can be achieved by means of more theoretical work, rather than by merely accumulating more data. To support our thesis, we introduce the analytic view of theory development, which rests on the concept of plausibility, and make clear in what sense plausibility and probability are distinct concepts. Then, the concept of plausibility is used to point out the ineliminable role played by the epistemic subject in the development of statistical tools and in the process of theory assessment. We then move to address a central issue in cancer research, namely the relevance of computational tools developed by bioinformaticists to detect driver mutations in the debate between the two main rival theories of carcinogenesis. Finally, we briefly extend our considerations on the role that plausibility plays in evidence amalgamation from cancer research to the more general issue of the divergences between frequentists and Bayesians in the philosophy of medicine and statistics. We argue that taking into account plausibility-based considerations can lead to clarify some epistemological shortcomings that afflict both these perspectives. probability and the concept of randomness concludes this part (section 2.8). In the second part of the paper (section 3), after having briefly illustrated the main rival conceptions of carcinogenesis (section 3.1), the notion of personalized cancer medicine (section 3.2), and the concept of driver mutations (section 3.3), we address some issues in cancer research to test the adequacy and fertility of the theoretical framework presented in the first part. More precisely, we focus on some of the computational tools that have been developed by bioinformaticists for searching driver mutations in cancer specimens (sections 3.4. and 3.5), in order to highlight the role played by plausibility-based considerations in the development of statistical tools and in the assessment of theoretical hypotheses (section 3.6). Finally, in the third part, we put the conclusions that can be drawn from our analysis in a broader context (section 4). We think that our proposal may be of use to address a more general issue, which characterizes both the philosophy of medicine and the philosophy of statistics, and which is also crucial for the epistemological investigations of cancer research, namely the confrontation between frequentists and Bayesians on what is the more adequate way to conceive of evidence amalgamation (sections 4.1, 4.2, and 4.3).

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“…This is the case of the Tissue Organization Field Theory (TOFT) [13,219,220]. According to TOFT, cancer is a problem of tissue organization that arises from disruption of the interactions between the cell and other tissue components.…”

Section: Discussionmentioning

confidence: 99%

The Stem Cell Division Theory of Cancer

López‐Lázaro

2017

Preprint

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All cancer registries constantly show striking differences in cancer incidence by age and among tissues. For example, lung cancer is diagnosed hundreds of times more often at age 70 than at age 20, and this cancer in nonsmokers occurs thousands of times more frequently than heart cancer in smokers. An analysis of these differences using basic concepts in cell biology indicates that cancer is the end-result of the accumulation of cell divisions in stem cells. In other words, the main determinant of carcinogenesis is the number of cell divisions that the DNA of a stem cell has accumulated in any type of cell from the zygote. Cell division, process by which a cell copies and separates its cellular components to finally split into two cells, is necessary to produce the large number of cells required for living. However, cell division can lead to a variety of cancer-promoting errors, such as mutations occurring during DNA replication, chromosome aberrations arising during mitosis, errors in the distribution of cell-fate determinants between the daughter cells, and failures to restore physical interactions with other tissue components. Some of these errors are spontaneous, others are promoted by endogenous DNA damage occurring during quiescence, and others are influenced by pathological and environmental factors. The cell divisions required for carcinogenesis are primarily caused by multiple local and systemic physiological signals rather than by errors in the DNA of the cells. As carcinogenesis progresses, the accumulation of DNA errors promotes cell division and eventually triggers cell division under permissive extracellular environments. The accumulation of cell divisions in stem cells drives not only the accumulation of the DNA alterations required for carcinogenesis, but also the formation and growth of the abnormal cell populations that characterize the disease. This model of carcinogenesis provides a new framework for understanding the disease and has important implications for cancer prevention and therapy.

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SMT and TOFT: Why and How They are Opposite and Incompatible Paradigms

Cited by 26 publications

References 124 publications

Cancer as a disorder of patterning information: computational and biophysical perspectives on the cancer problem

Cancer as a disorder of patterning information: computational and biophysical perspectives on the cancer problem

Evidence amalgamation, plausibility, and cancer research

The Stem Cell Division Theory of Cancer

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