Beyond the Oncogene Paradigm: Understanding Complexity in Cancerogenesis

Abstract

In the past decades, an enormous amount of precious information has been collected about molecular and genetic characteristics of cancer. This knowledge is mainly based on a reductionistic approach, meanwhile cancer is widely recognized to be a 'system biology disease'. The behavior of complex physiological processes cannot be understood simply by knowing how the parts work in isolation. There is not solely a matter how to integrate all available knowledge in such a way that we can still deal with complexity, but we must be aware that a deeply transformation of the currently accepted oncologic paradigm is urgently needed. We have to think in terms of biological networks: understanding of complex functions may in fact be impossible without taking into consideration influences (rules and constraints) outside of the genome. Systems Biology involves connecting experimental unsupervised multivariate data to mathematical and computational approach than can simulate biologic systems for hypothesis testing or that can account for what it is not known from high-throughput data sets. Metabolomics could establish the requested link between genotype and phenotype, providing informations that ensure an integrated understanding of pathogenic mechanisms and metabolic phenotypes and provide a screening tool for new targeted drug.

Cancer as a disorder of patterning information: computational and biophysical perspectives on the cancer problem

“…A competing perspective is that of cancer as a circuit disease-a disorder of the complex biophysical, transcriptional, and epigenetic dynamics that regulate cellular state and the ability of cells to cooperate in vivo [6][7][8]. Under this view (sometimes called the tissue organization field theory or TOFT, [9,10]), cancer is akin to a traffic jam [11]-the problem is not a permanent discrete alteration within a founder cell and all of its clonal descendants, but an undesirable stable attractor in the complex network of controls that normally guides anatomical homeostasis [12].The relative merits of the two models have been discussed extensively [10,[13][14][15][16][17] …”

Modelling Physiological and Pharmacological Control on Cell Proliferation to Optimise Cancer Treatments

“…Rather, A. Soto and C. Sonnenschein, in a series of articles [188,248,249,247,250] advocate the preeminence of the surrounding stroma in carcinogenesis, opposing their tissue organisation field theory (non clonal origin of cancer) to the classical somatic mutation theory (clonal origin). A close view is also discussed, with many references, in [31].…”

“…Rather, A. Soto and C. Sonnenschein, in a series of articles [188,248,249,247,250] advocate the preeminence of the surrounding stroma in carcinogenesis, opposing their tissue organisation field theory (non clonal origin of cancer) to the classical somatic mutation theory (clonal origin). A close view is also discussed, with many references, in [31].Being in no position to take part in this theoretical biology dispute, I will only remark that the tissue organization field theory seems to be consistent with evolutionary theories transposing Darwinism to the cellular field [155,156] to yield an ontophylogenetic point of view [157] that is in accordance with the fact that the same mechanisms (in particular "sculpture of the living" by apoptosis [10], see also [195,196] on netrin-1 DCC receptors) are often present in both carcinogenesis and organogenesis, the former, contrasting with the latter, being of course out of local tissue control. Can these opposed views be reconciled?…”

Systems biology reveals biology of systems

“…It is even clearer that not genes, nor proteins, nor metabolites but their connections are the key points of main questions addressed by biological science in the last century. Depending on their hierarchical organization, clinical and experimental evidences reveal the complexity of important diseases and biological systems [11]. Systems Biology might then provide a new outcome, which is not merely a more refined picture, addressing a different level of understanding.…”