1. Cancer Biology
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Philosophy of Biology: Characterizing causality in cancer

  1. Elena Rondeau
  2. Nicolas Larmonier
  3. Thomas Pradeu  Is a corresponding author
  4. Andreas Bikfalvi  Is a corresponding author
  1. University of Bordeaux, France
  2. CNRS UMR 5164, France
  3. CNRS UMR 8590, France
  4. LAMC-INSERM U1029, France
Feature Article
Cite this article as: eLife 2019;8:e53755 doi: 10.7554/eLife.53755
2 figures


Two theories of tumor formation.

In the somatic mutation theory (SMT; left) the default state of the cell is quiescence, and a genetic event in the cell triggers a unidirectional, irreversible and deterministic process that leads to tumor expansion and dissemination. In the tissue organization field theory (TOFT; right), the default state of the cell is proliferation, and a disruption of the tissue architecture leads to the diffusion of various mutations within the tumor and to the activation of the tumor microenvironment (TME). Through feedback mechanisms, this leads to further disruption of the tissue architecture, which promotes tumor expansion and dissemination.

The influence of tumor-cell-intrinsic and tumor-cell-extrinsic factors on tumor formation and the dissemination of tumor cells.

The main steps in the progression of cancer (carcinogenesis and the three steps of dissemination) are shown in the center panels, along with the key tumor-cell-intrinsic factors (top; blue text) and tumor-cell-extrinsic factors (bottom; grey text) that influence progression. We will use step 2 of dissemination to explain the different types of causal relationships proposed in the figure. An example of an intrinsic factor acting at a given step (a type 'a' event) is the formation of clusters of tumor cells to enhance migration efficiency (2a, top), and an example of an extrinsic factor is the protection provided by vascular elements against immune attack and physical stress, during the same step (2a, bottom). Events during a given step can also exert an influence on a later step (type 'b' events): for instance, the initiation of the epithelial-to-mesenchymal transition (EMT) during step 1 of dissemination triggers the possibility of long-distance circulation in step 2 (2b, top). Events during a given step can also exert an influence on an earlier step (type 'c' events): for instance, the elements in the secondary tumor microenvironment (TME), which are part of step 3 of dissemination, also act as attractors for cancer cells during step 2 (2c, bottom). PMN: pre-metastatic niche.

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