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Is cancer a disease set up by cellular stress responses?

Abstract

For several decades, the somatic mutation theory (SMT) has been the dominant paradigm on cancer research, leading to the textbook notion that cancer is fundamentally a genetic disease. However, recent discoveries indicate that mutations, including “oncogenic” ones, are widespread in normal somatic cells, suggesting that mutations may be necessary but not sufficient for cancer to develop. Indeed, a fundamental but as yet unanswered question is whether or not the first step in oncogenesis corresponds to a mutational event. On the other hand, for some time, it has been acknowledged the important role in cancer progression of molecular processes that participate in buffering cellular stress. However, their role is considered secondary or complementary to that of putative oncogenic mutations. Here we present and discuss evidence that cancer may have its origin in epigenetic processes associated with cellular adaptation to stressful conditions, and so it could be a direct consequence of stress-buffering mechanisms that allow cells with aberrant phenotypes (not necessarily associated with genetic mutations) to survive and propagate within the organism. We put forward the hypothesis that there would be an inverse correlation between the activation threshold of the cellular stress responses (CSRs) and the risk of cancer, so that species or individuals with low-threshold CSRs will display a higher incidence or risk of cancer.

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Notes

  1. This theory suggests that induced or spontaneous mutations in critical genes accumulate within the genome of a given somatic cell that becomes transformed as a consequence of this, and as such, it becomes the founder of a clone of transformed cells. Then further mutations in further genes occur in such transformed cells, and those cells with mutations resulting in a selective “growth advantage” are further selected, thus giving origin to new clones that compete for space and resources in a sort of Darwinian evolutionary process, leading to the appearance of clones able to invade other tissues and furthermore, to spread elsewhere (metastasize) within the organism (Cairns 1975; Nowell 1976; Fearon and Vogelstein 1990; Stratton et al. 2009).

  2. In dynamical systems, an attractor state is a set of points or values toward which the system evolves from a wide variety of initial conditions. The attractor state constitutes a preferential stable regime for the system. In cells, the concept of attractor has been applied to cellular phenotypes and to the internal gene regulatory network (Huang et al. 2009; Aranda-Anzaldo and Dent 2018).

  3. Hormesis refers to any process that exhibits a biphasic response to a substance or environmental condition characterized by a low-dose stimulation or beneficial effect and a high-dose inhibitory or toxic effect (Mattson 2008). Hormesis is an important concept within evolutionary theory as organisms should develop complex mechanisms for coping with environmental hazards. It is a fact that several chaperones associated with the heat shock response participate in the cellular hormetic response (Mattson 2008). Many carcinogens behave as hormetic compounds that induce the stress response at low dose and given their cytotoxic effects, kill cells at high dose. Interestingly, experiments of cell transformation in vitro by exposure to X-rays indicate that the yield of transformed foci increases as a function of the dose up to 400 rads. Yet, further increases in the dose up to 1400 rads result in augmented cell mortality but negligible or null increase in the yield of transformed foci from the surviving cells (Terzaghi and Little 1976).

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Acknowledgements

We thank the anonymous referees for their comments and suggestions for improving the manuscript.

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This work was supported by Universidad Autónoma del Estado de México grant no. 4971/2020CIB. The funding source had no role in the preparation of the manuscript or in the decision to publish it.

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A Aranda-Anzaldo: conceptualization, investigation, writing—original draft, funding acquisition. MAR Dent: investigation, writing—reviewing and editing, funding acquisition.

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Correspondence to Armando Aranda-Anzaldo.

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Aranda-Anzaldo, A., Dent, M.A.R. Is cancer a disease set up by cellular stress responses?. Cell Stress and Chaperones 26, 597–609 (2021). https://doi.org/10.1007/s12192-021-01214-4

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  • DOI: https://doi.org/10.1007/s12192-021-01214-4

Keywords

  • Heat shock response
  • Hormesis
  • Phenotypic selection
  • Physiological adaptation
  • Peto’s paradox
  • Protein folding
  • Unfolded protein response