How Understand the Nature of Cancer?

For a century, the somatic mutation theory (SMT) has been the prevalent theory to explain carcino-genesis. According to the SMT, cancer is a cellular problem, and thus, the level of organization where it should be studied is the cellular level. Additionally, the SMT proposes that cancer is a problem of the control of cell proliferation and assumes that proliferative quiescence is the default state of cells in metazoa. In 1999, a competing theory, the tissue organization field theory (TOFT), was proposed. In contraposition to the SMT, the TOFT posits that cancer is a tissue-based disease whereby carcinogens (directly) and mutations in the germ-line (indirectly) alter the normal interactions between the diverse components of an organ, such as the stroma and its adjacent epithelium. The TOFT explicitly acknowledges that the default state of all cells is proliferation with variation and motility. When taking into consideration the principle of organization, we posit that carcinogenesis can be explained as a relational problem whereby release of the constraints created by cell interactions and the physical forces generated by cellular agency lead cells within a tissue to regain their default state of proliferation with variation and motility. Within this perspective, what matters both in morphogenesis and carcinogenesis is not only molecules, but also biophysical forces generated by cells and tissues. Herein, we describe how the principles for a theory of organisms apply to the TOFT and thus to the study of carcinogenesis.

Frontiers in Oncology, 2017

Experimental paradigms provide the framework for the understanding of cancer, and drive research and treatment, but are rarely considered by clinicians. The somatic mutation theory (SMT), in which cancer is considered a genetic disease, has been the predominant traditional model of cancer for over 50 years. More recently, alternative theories have been proposed, such as tissue organization field theory (TOFT), evolutionary models, and inflammatory models. Key concepts within the various models have led to them being difficult to reconcile. Progressively, it has been recognized that biological systems cannot be fully explained by the physicochemical properties of their constituent parts. There is an increasing call for a ‘systems’ approach. Incorporating the concepts of ‘emergence’, ‘systems’, ‘thermodynamics’, and ‘chaos’, a single integrated framework for carcinogenesis has been developed, enabling existing theories to become compatible as alternative mechanisms, facilitating the integration of bioinformatics and providing a structure in which translational research can flow from both ‘benchtop to bedside’ and ‘bedside to benchtop’. In this review, a basic understanding of the key concepts of ‘emergence’, ‘systems’, ‘system levels’, ‘complexity’, ‘thermodynamics’, ‘entropy’, ‘chaos’, and ‘fractals’ is provided. Non-linear mathematical equations are included where possible to demonstrate compatibility with bioinformatics. Twelve principles that define the ‘emergence framework of carcinogenesis’ are developed, with principles 1–10 encapsulating the key concepts upon which the framework is built and their application to carcinogenesis. Principle 11 relates the framework to cancer progression. Principle 12 relates to the application of the framework to translational research. The ‘emergence framework of carcinogenesis’ collates current paradigms, concepts, and evidence around carcinogenesis into a single framework that incorporates previously incompatible viewpoints and ideas. Any researcher, scientist, or clinician involved in research, treatment, or prevention of cancer can employ this framework.

The theory of somatic mutations is incorrect, and the concept of "mutation" is incorrectly used. Etiological classification of tumors: 1) Tumors of malignant proliferation. Tumor cells are not specific. Tumor growth of malignant proliferation is provided by the reproduction of normal cells. The trigger mechanism of division is the interrelated actions of all the constituent parts of the tissue. The tumor mass increases due to the division of normal cells during its stimulation and dysfunction of its inhibitors and due to the predominance of cell proliferation over apoptosis. Calcium contributes to the formation of an independent structure. A tumor is a hierarchical system of its tissue and distant parts (metastases) that carry out the mutual influence. 2) Transgenic (infectious) tumors -a hybrid of a somatic cell and a microbe. They may be contagious. 3) Gestational tumors. 4) Tumors of genetic aberrations.

Journal of Biosciences, 2005

During the last fifty years the dominant stance in experimental biology has been reductionism. For the most part, research programs were based on the notion that genes were in 'the driver's seat' controlling the developmental program and determining normalcy and disease (genetic reductionism and genetic determinism). Philosophers were the first to realize that the belief that the Mendelian genes were reduced to DNA molecules was questionable. Soon after these pronouncements, experimental data confirmed their misgivings. The optimism of molecular biologists, fueled by early success in tackling relatively simple problems, has now been tempered by the difficulties found when attempting to understand complex biological problems.

Background: Current biologic research is based on a reductionist approach. Complex systems are broken down into combinations of simpler systems or parts, which can then be studied more readily. Although this approach is rational, it has failed to bring about the understanding necessary to substantially reduce cancer-related deaths. Complexity theory suggests that emergent properties, based on interactions between the parts, are important in understanding fundamental features of living systems. Applying complexity theory to neoplasia may yield a greater understanding of physiologic systems that have gone awry. The laws of complexity and self-organization are reviewed and summarized, and applied to neoplasia: 1. In living systems, the whole is greater than the sum of the parts. 2. There is an inherent inability to predict the future, particularly for living systems. 3. Life emerges when the molecular diversity of a closed system exceeds a threshold of complexity. 4. Much of the order in organisms is due to generic properties that emerge from a network of gene products. 5. Numerous biologic pressures push cells towards disorder. 6. Organisms resist these biologic pressures towards disorder through multiple layers of redundant controls. 7. Neoplasia occurs as these multiple controls are breached. The resulting neoplastic process reflects the nature of the breaches, the individual's germline configuration and the network state of the cell of origin. In the framework of the laws of complexity and self-organization, cells maintain order by redundant control features that resist the inherent biologic pressure in the cell towards disorder. Neoplasia can be understood as the accumulation of changes that undermine these control features, which may lead to dysregulated growth and differentiation. Studying the neoplastic process within this context may generate new approaches to treatment.

Proceedings of the National Academy of …, 1973

A general hypothesis of carcinogenesis is proposed consisting of the following features: (1) It is suggested that all cells possess multiple structural genes (Tr) capable of coding for transforming factors which can

Seminars in Cancer Biology, 2008

Four decades ago Leslie Foulds remarked that "Experimental analysis has produced an alarming mass of empirical facts without providing an adequate language for their communication or effective concepts for their synthesis". Examining the relevance of the data avalanche we all generate and are subjected to in the context of the premises and predictions of the current cancer theories may help resolve this paradox. This goal is becoming increasingly relevant given the looming attempts to rigorously model and parameterize crucial events in carcinogenesis (microenvironmental conditions, cellular proliferation and motility), which will require the adoption of reliable premises on which to base those efforts. This choice must be made a priori, as premises are not testable, and data are not free of the theoretical frame used to gather them. In this review we provide a critical analysis of the two main currents in cancer research, one centered at the cellular level of biological organization, the somatic mutation theory, which conceptualizes carcinogenesis as a problem of cell proliferation control, and the other centered at the tissue level, the tissue organization filed theory, which considers carcinogenesis a process akin to organogenesis gone awry.

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.