The mysterious steps in carcinogenesis

Brash, Douglas E.; Cairns, John

doi:10.1038/sj.bjc.6605171

Cited by 28 publications

(23 citation statements)

References 19 publications

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“…Because the SMT relies on DNA mutations in the founder cell that would become cancerous, in carcinomas this cell is an epithelial one 3 . Thus, while the core narrative of the SMT has remained intact, increasingly pointed criticisms due to the difficulties in fitting data within the premises of the theory are addressed by ad hoc additions or become labeled as “mysterious steps” [9]. More specifically, Brash and Cairns state: “The prime mystery in carcinogenesis remains the very first step, because it is hard to imagine how the numerous genetic changes found in cancer cells could have been produced in any cell as the result of a single exposure to a DNA-damaging agent, or why months or years should have to elapse before the effect of these changes is observed”.…”

Section: Failings Of the Smtmentioning

confidence: 99%

“…This latter interpretation, as well as the competing SMT, has faced many challenges over the years due to the lack of an agreed comprehensive explanation of how cancer fits within biology at large. Faced with the complexity of human cancer, some have suggested that “…a new idea seems to be needed… to start to clarify what is going on during carcinogenesis” [9]. Based on this suggestion, an evaluation of the usefulness of the SMT and of alternative approaches to it is due.…”

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confidence: 99%

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The tissue organization field theory of cancer: A testable replacement for the somatic mutation theory

Soto¹,

2011

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The somatic mutation theory (SMT) of cancer has been and remains the prevalent theory attempting to explain how neoplasms arise and progress. This theory proposes that cancer is a clonal, cell-based disease, and implicitly assumes that quiescence is the default state of cells in multicellular organisms. The SMT has not been rigorously tested, and several lines of evidence raise questions that are not addressed by this theory. Herein, we propose experimental strategies that may validate the SMT. We also call attention to an alternative theory of carcinogenesis, the tissue organization field theory (TOFT), which posits that cancer is a tissue-based disease and that proliferation is the default state of all cells. Based on epistemological and experimental evidence, we argue that the TOFT compellingly explains carcinogenesis, while placing it within an evolutionarily relevant context.

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Section: Failings Of the Smtmentioning

confidence: 99%

mentioning

confidence: 99%

The tissue organization field theory of cancer: A testable replacement for the somatic mutation theory

Soto¹,

2011

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“…The low growth-promoting activity of interstitial fluids would also account for the relatively large increase in cancer with prolonged increases in growth-stimulating hormones [35]. Given the evidence that selection is the driving force in human carcinogenesis [28,29], and the strong promoting effect of increased saturation density evident here, the driving force of increased cell division would not be increased mutation [35][36][37], but increased opportunities for selection of existing mutations [25,27,38,39]. Evidence for field effects in carcinogenesis of the lung, colon, breast, and other cancers have been cited by Braakhuis et al [7], and the general rules developed here should be applicable with appropriate modification to each special case.…”

Section: Discussionmentioning

confidence: 96%

Fields and field cancerization: The preneoplastic origins of cancer

Rubin

2011

BioEssays

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Most basic research on cancer concerns genetic changes in benign and malignant tumors. Yet evidence indicates that the majority of the mutations in tumors occur in the preneoplastic field stage of their development. That early stage is represented by grossly invisible, broad regions of "field cancerization" which have not, heretofore, been operationally analyzed in cell culture. Conditions are described for quantitating preneoplasia by increased saturation density followed by progression to transformation. These parameters are driven by Darwinian selection of spontaneously occurring, cumulative mutations, in accordance with recent genomic analyses of human cancer, just as it is in the evolution of species. The cell culture model will allow correlation of the preneoplastic increases in saturation density with genetic changes, and development of methods for demarcating fields during surgery so that they can be excised along with the tumor, thereby reducing the possibility of recurrence at the site.

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“…Despite having acquired massive amounts of data about epithelial cancers at the molecular and cellular level, little is known about how carcinogenesis occurs (Brash and Cairns 2009). Mainstream thought claims that cancer is a problem of regulatory control of cell proliferation due to the genetic/epigenetic mutation within one or several initiating cells (Dalerba et al 2007).…”

Section: Introductionmentioning

confidence: 98%

Tissue normalizing capacity as a key determinant of carcinogenesis: an in silico simulation

Cao

2014

Biotechnol Lett

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A perturbed microenvironment is at the core of carcinogenesis. Here, we used a 2D cellular automata model to simulate how cancers are generated in epithelial tissue. We applied several mathematical rules to simulate tissue renewal and surrounding cell control. Under the simulation, we showed that the average value of surrounding normal cells could be an indicator for the tissue normalizing capacity (TNC). Further, we found the incidence of carcinogenesis correlated inversely with the TNC. Interestingly, we also found that multi-round mutagenesis could gradually disturb the TNC when compared to one-round mutagenesis: cancer incidence increased significantly compared to one-round mutagenesis. Our model suggests that the genetic alterations (mutations) by themselves were not sufficient to initiate cancer. The perturbation of TNC could be a key process leading to carcinogenesis.

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The mysterious steps in carcinogenesis

Cited by 28 publications

References 19 publications

The tissue organization field theory of cancer: A testable replacement for the somatic mutation theory

The tissue organization field theory of cancer: A testable replacement for the somatic mutation theory

Fields and field cancerization: The preneoplastic origins of cancer

Tissue normalizing capacity as a key determinant of carcinogenesis: an in silico simulation

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