Of criminals and cancer: The importance of social bonds and innate morality on cellular societies.

The current dogma in cancer biology contends that cancer is an identity problem: mutations in a cell's DNA cause it to "go rogue" and proliferate out of control. However, this largely ignores the role of cell-cell interaction and fails to explain phenomena such as cancer reversion, the existence of cancers without mutations, and foreign-body carcinogenesis. In this proof-of-concept paper, we draw on criminology to propose that cancer may alternatively be conceptualized as a relational problem: Although a cell's genetics is essential, the influence of its interaction with other cells is equally important in determining its phenotype. We create a simple agent-based network model of interactions among normal and cancer cells to demonstrate this idea. We find that both high mutation rates and low levels of connectivity among cells can promote oncogenesis. Viewing cancer as a breakdown in communication networks among cells in a tissue complements the gene-centric paradigm nicely and provides a novel perspective for understanding and treating cancer.

Normalizing Input-Output Relationships of Cancer Networks for Reversion Therapy.

Accumulated genetic alterations in cancer cells distort cellular stimulus-response (or input-output) relationships, resulting in uncontrolled proliferation. However, the complex molecular interaction network within a cell implicates a possibility of restoring such distorted input-output relationships by rewiring the signal flow through controlling hidden molecular switches. Here, a system framework of analyzing cellular input-output relationships in consideration of various genetic alterations and identifying possible molecular switches that can normalize the distorted relationships based on Boolean network modeling and dynamics analysis is presented. Such reversion is demonstrated by the analysis of a number of cancer molecular networks together with a focused case study on bladder cancer with in vitro experiments and patient survival data analysis. The origin of reversibility from an evolutionary point of view based on the redundancy and robustness intrinsically embedded in complex molecular regulatory networks is further discussed.

Paradoxical Behavior of Oncogenes Undermines the Somatic Mutation Theory.

The currently accepted theory on the influence of DNA mutations on carcinogenesis (the Somatic Mutation Theory, SMT) is facing an increasing number of controversial results that undermine the explanatory power of mutated genes considered as "causative" factors. Intriguing results have demonstrated that several critical genes may act differently, as oncogenes or tumor suppressors, while phenotypic reversion of cancerous cells/tissues can be achieved by modifying the microenvironment, the mutations they are carrying notwithstanding. Furthermore, a high burden of mutations has been identified in many non-cancerous tissues without any apparent pathological consequence. All things considered, a relevant body of unexplained inconsistencies calls for an in depth rewiring of our theoretical models. Ignoring these paradoxes is no longer sustainable. By avoiding these conundrums, the scientific community will deprive itself of the opportunity to achieve real progress in this important biomedical field. To remedy this situation, we need to embrace new theoretical perspectives, taking the cell-microenvironment interplay as the privileged pathogenetic level of observation, and by assuming new explanatory models based on truly different premises. New theoretical frameworks dawned in the last two decades principally focus on the complex interaction between cells and their microenvironment, which is thought to be the critical level from which carcinogenesis arises. Indeed, both molecular and biophysical components of the stroma can dramatically drive cell fate commitment and cell outcome in opposite directions, even in the presence of the same stimulus. Therefore, such a novel approach can help in solving apparently inextricable paradoxes that are increasingly observed in cancer biology.

Resolution of Complex Issues in Genome Regulation and Cancer Requires Non-Linear and Network-Based Thermodynamics.

The apparent lack of success in curing cancer that was evidenced in the last four decades of molecular medicine indicates the need for a global re-thinking both its nature and the biological approaches that we are taking in its solution. The reductionist, one gene/one protein method that has served us well until now, and that still dominates in biomedicine, requires complementation with a more systemic/holistic approach, to address the huge problem of cross-talk between more than 20,000 protein-coding genes, about 100,000 protein types, and the multiple layers of biological organization. In this perspective, the relationship between the chromatin network organization and gene expression regulation plays a fundamental role. The elucidation of such a relationship requires a non-linear thermodynamics approach to these biological systems. This change of perspective is a necessary step for developing successful 'tumour-reversion' therapeutic strategies.

Unravelling the complexity of signalling networks in cancer: A review of the increasing role for computational modelling.

Cancer induction is a highly complex process involving hundreds of different inducers but whose eventual outcome is the same. Clearly, it is essential to understand how signalling pathways and networks generated by these inducers interact to regulate cell behaviour and create the cancer phenotype. While enormous strides have been made in identifying key networking profiles, the amount of data generated far exceeds our ability to understand how it all "fits together". The number of potential interactions is astronomically large and requires novel approaches and extreme computation methods to dissect them out. However, such methodologies have high intrinsic mathematical and conceptual content which is difficult to follow. This review explains how computation modelling is progressively finding solutions and also revealing unexpected and unpredictable nano-scale molecular behaviours extremely relevant to how signalling and networking are coherently integrated. It is divided into linked sections illustrated by numerous figures from the literature describing different approaches and offering visual portrayals of networking and major conceptual advances in the field. First, the problem of signalling complexity and data collection is illustrated for only a small selection of known oncogenes. Next, new concepts from biophysics, molecular behaviours, kinetics, organisation at the nano level and predictive models are presented. These areas include: visual representations of networking, Energy Landscapes and energy transfer/dissemination (entropy); diffusion, percolation; molecular crowding; protein allostery; quinary structure and fractal distributions; energy management, metabolism and re-examination of the Warburg effect. The importance of unravelling complex network interactions is then illustrated for some widely-used drugs in cancer therapy whose interactions are very extensive. Finally, use of computational modelling to develop micro- and nano- functional models ("bottom-up" research) is highlighted. The review concludes that computational modelling is an essential part of cancer research and is vital to understanding network formation and molecular behaviours that are associated with it. Its role is increasingly essential because it is unravelling the huge complexity of cancer induction otherwise unattainable by any other approach.

Quantitative evaluation and reversion analysis of the attractor landscapes of an intracellular regulatory network for colorectal cancer.

BACKGROUND: Cancer reversion, converting the phenotypes of a cancer cell into those of a normal cell, has been sporadically observed throughout history. However, no systematic analysis has been attempted so far. RESULTS: To investigate this from a systems biological perspective, we have constructed a logical network model of colorectal tumorigenesis by integrating key regulatory molecules and their interactions from previous experimental data. We identified molecular targets that can reverse cancerous cellular states to a normal state by systematically perturbing each molecular activity in the network and evaluating the resulting changes of the attractor landscape with respect to uncontrolled proliferation, EMT, and stemness. Intriguingly, many of the identified targets were well in accord with previous studies. We further revealed that the identified targets constitute stable network motifs that contribute to enhancing the robustness of attractors in cancerous cellular states against diverse regulatory signals. CONCLUSIONS: The proposed framework for systems analysis is applicable to the study of tumorigenesis and reversion of other types of cancer.

Attractor landscape analysis of colorectal tumorigenesis and its reversion.

BACKGROUND: Colorectal cancer arises from the accumulation of genetic mutations that induce dysfunction of intracellular signaling. However, the underlying mechanism of colorectal tumorigenesis driven by genetic mutations remains yet to be elucidated. RESULTS: To investigate colorectal tumorigenesis at a system-level, we have reconstructed a large-scale Boolean network model of the human signaling network by integrating previous experimental results on canonical signaling pathways related to proliferation, metastasis, and apoptosis. Throughout an extensive simulation analysis of the attractor landscape of the signaling network model, we found that the attractor landscape changes its shape by expanding the basin of attractors for abnormal proliferation and metastasis along with the accumulation of driver mutations. A further hypothetical study shows that restoration of a normal phenotype might be possible by reversely controlling the attractor landscape. Interestingly, the targets of approved anti-cancer drugs were highly enriched in the identified molecular targets for the reverse control. CONCLUSIONS: Our results show that the dynamical analysis of a signaling network based on attractor landscape is useful in acquiring a system-level understanding of tumorigenesis and developing a new therapeutic strategy.