Competing views on cancer

Abstract

Despite intense research efforts that have provided enormous insight, cancer continues to be a poorly understood disease. There has been much debate over whether the cancerous state can be said to originate in a single cell or whether it is a reflection of aberrant behaviour on the part of a 'society of cells'. This article presents, in the form of a debate conducted among the authors, three views of how the problem might be addressed. We do not claim that the views exhaust all possibilities. These views are (a) the tissue organization field theory (TOFT) that is based on a breakdown of tissue organization involving many cells from different embryological layers, (b) the cancer stem cell (CSC) hypothesis that focuses on genetic and epigenetic changes that take place within single cells, and (c) the proposition that rewiring of the cell's protein interaction networks mediated by intrinsically disordered proteins (IDPs) drives the tumorigenic process. The views are based on different philosophical approaches. In detail, they differ on some points and agree on others. It is left to the reader to decide whether one approach to understanding cancer appears more promising than the other.

Figure 1

Carcinogenesis according to the TOFT. A single or multiple carcinogenic exposure acts, disturbing the reciprocal biophysical and biomechanical communication between the parenchyma and the mesenchyme/stroma in a given morphogenetic field. This results in miscues that manifest morphologically in both the stroma and the epithelium. The proliferation and motility restraints imposed by normal tissue architecture loosen and, as a consequence, hyperplasia of the epithelium may occur. Further alteration of the reciprocal interactions between tissue compartments will induce metaplasia, dysplasia, and carcinoma. The stroma also may show alterations (desmoplasia, inflammatory cells).

Figure 2

Illustration of SMT and TOFT models: (a) The SMT posits that carcinogens lead to mutations in the cellular DNA of epithelial cells, leading to propagation of cells carrying advantageous mutations. Paracrine factors secreted by the growing tumour alter the tumour stroma. The altered or ‘activated’ stroma in turn contributes to cancer progression, enabling a conducive environment for tumour cell invasion and metastasis. (b) The TOFT model predicts that carcinogens affect the stroma, leading to altered cell–ECM and cell–cell interactions in the epithelium, which then results in tumour formation in the epithelium.

Figure 3

Schematic of mammary gland fat pad transplantation experiments.

Figure 4

Hierarchical organization of cells within tissues: (a) Self-renewing adult tissues contain few ‘stem cells’ that divide to make more of themselves (by self-renewal) and also generate cells of more restricted potential – the ‘progenitors or transit amplifying cells’ – which undergo few rounds of rapid proliferation to finally generate the committed/differentiated cells of the tissue. (b) Cancer stem cells occupy the tip of the hierarchy within cancers, with capability to undergo self-renewal, and ‘differentiation’ to generate the bulk of the tumour cells.

Figure 5

A Myc sub-network showing its interactions with multiple partners. Myc represents the central hub in the protein interaction network. The image is obtained by accessing the data from the STRING protein interaction database (http://string-db.org/). The proteins that are not predicted to be intrinsically disordered are circled in red. The others, including Myc, are predicted to be intrinsically disordered.

Figure 6

Cancer, evolution, and intrinsically disordered proteins. The cancer cell is regarded as a nonlinear system characterized by protein interaction networks (PINs) with dynamic topologies. (a) The coloured balls (nodes) connected by solid lines (edges) within each cell (large circles and squares) represent the PINs. Individual cells in a tumour interact and self-organize forming an ensemble of complex interactive parts with emergent properties. The macroscopic behaviour of the system such as state/phenotype switching (e.g. malignant transformation) in response to extrinsic perturbation depends on the type and strength of interaction among the constitutive cells and their response to external perturbations leading to different types of synchronized emergent dynamics. (b) The latter results from rewiring and synchronization of PINs in the ensemble. Intrinsically disordered proteins (IDPs) that are overexpressed in cancer drive this process by exploring the search space and rewiring the PINs (represented by different configurations in each of the cells a1, a2, a3, etc., in phenotype A). (c) Rewiring of PINs results in unmasking latent pathways that facilitate state switching (e.g. phenotype A to phenotype B) in some cells within the population (e.g. a7) and their subsequent proliferation (b1, b2, b3, etc.).