Over a century of cancer research: Inconvenient truths and promising leads

Sonnenschein, Carlos; Soto, Ana M.

doi:10.1371/journal.pbio.3000670

Cited by 51 publications

(36 citation statements)

References 94 publications

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“…The alteration in the interplay among those components involves different levels of organization and a number of secondary changes, eventually including the emergence of disrupted gene-expression patterns. In agreement with TOFT, mutated genes are the result, and not the cause, of the disrupted normal tissue architecture that eventually ends up in fostering cancer onset [57]. Therefore, changes in genomic profiles or in biochemical pathways can only be "associated" rather than considered as "causative."…”

Section: Inadequacies Of Theoretical Assumptions At the Root Of The Personalized Medicinementioning

confidence: 92%

Personalization of medical treatments in oncology: time for rethinking the disease concept to improve individual outcomes

et al. 2021

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The agenda of pharmacology discovery in the field of personalized oncology was dictated by the search of molecular targets assumed to deterministically drive tumor development. In this perspective, genes play a fundamental “causal” role while cells simply act as causal proxies, i.e., an intermediate between the molecular input and the organismal output. However, the ceaseless genomic change occurring across time within the same primary and metastatic tumor has broken the hope of a personalized treatment based only upon genomic fingerprint. Indeed, current models are unable in capturing the unfathomable complexity behind the outbreak of a disease, as they discard the contribution of non-genetic factors, environment constraints, and the interplay among different tiers of organization. Herein, we posit that a comprehensive personalized model should view at the disease as a “historical” process, in which different spatially and timely distributed factors interact with each other across multiple levels of organization, which collectively interact with a dynamic gene-expression pattern. Given that a disease is a dynamic, non-linear process — and not a static-stable condition — treatments should be tailored according to the “timing-frame” of each condition. This approach can help in detecting those critical transitions through which the system can access different attractors leading ultimately to diverse outcomes — from a pre-disease state to an overt illness or, alternatively, to recovery. Identification of such tipping points can substantiate the predictive and the preventive ambition of the Predictive, Preventive and Personalized Medicine (PPPM/3PM). However, an unusual effort is required to conjugate multi-omics approaches, data collection, and network analysis reconstruction (eventually involving innovative Artificial Intelligent tools) to recognize the critical phases and the relevant targets, which could help in patient stratification and therapy personalization.

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Section: Inadequacies Of Theoretical Assumptions At the Root Of The Personalized Medicinementioning

confidence: 92%

Personalization of medical treatments in oncology: time for rethinking the disease concept to improve individual outcomes

et al. 2021

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“…The present hypothesis has many contact points with the Tissue Organization Field Theory (TOFT) 32 , 33 , in the sense that it considers cancer a disease of tissue organization, and a tumor can originate from a perturbation on the tissue environment, not of a single or reduced number of cells, leading to a transition from normal to pluripotent like cells 34 . The bioelectrical communication is then a mechanism for tissue cells homeostasis but also, in case of a major perturbation, a process driving a global cells’ state change.…”

Section: Bioelectric Bistability and Carcinogenesismentioning

confidence: 99%

A bioelectric model of carcinogenesis, including propagation of cell membrane depolarization and reversal therapies

Carvalho

2021

Sci Rep

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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.

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“…This is a key issue because several conditions may affect the composition and the biophysical properties of the microenvironment, which can consequently foster CSK remodeling and thus adaptive change in gene expression and cell phenotype. Focusing on the microenvironment would implies we should switch from a cell-centered perspective toward a wide, systems-based view given that the complex crosstalk in between cells and stroma is ultimately responsible for those processes that involve tissue morphogenesis and its pathological outcomes, like cancer (Sonnenschein and Soto, 2020).…”

Section: The Backgroundmentioning

confidence: 99%

“…Under gravity, striped patterns of microtubules oriented consecutively in an ordered manner, whereas in weightlessness, no pattern formation arises and microtubules self-organize into an isotropic configuration without preferential orientation. In other words, gravity provides a vector of directionality to the self-organizing process (Lim and Plachta, 2021;Sonnenschein and Soto, 2020). Ultimately, the non-equilibrium dynamics modulation of CSK allows cells to display emergent properties, long range correlations and dramatic first-order classes transitions.…”

Section: The Impact Of the Novel Paradigmmentioning

confidence: 99%

Microenvironment promotes cytoskeleton remodeling and adaptive phenotypic transition

Bizzarri¹,

Pontecorvi²

2022

Biocell

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The cytoskeleton includes three main classes of networked filaments behaving as a coherent and complex structure that confers stability to cell shape while serving as sensor of internal/extracellular changes.Microenvironmental stimuli interfere with the non-linear dynamics that govern cytoskeleton architecture, namely by fostering symmetry breakings and transitions across different phenotypic states. Such process induces a wholecoherent adaptive response, involving the reprogramming of biochemical and gene-expression patterns. These characteristics are especially relevant during development, and in those conditions in which a deregulated crosstalk between cells and the stroma is at the core of the pathological process. Therefore, studying how the cytoskeleton can be modified-both pharmacologically and/or through microenvironment-dependent changes-has become a major area of interest in cancer and developmental biology.

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Over a century of cancer research: Inconvenient truths and promising leads

Cited by 51 publications

References 94 publications

Personalization of medical treatments in oncology: time for rethinking the disease concept to improve individual outcomes

Personalization of medical treatments in oncology: time for rethinking the disease concept to improve individual outcomes

A bioelectric model of carcinogenesis, including propagation of cell membrane depolarization and reversal therapies

Microenvironment promotes cytoskeleton remodeling and adaptive phenotypic transition

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