alexa Energy management - a critical role in cancer induction?
Pharmaceutical Sciences

Pharmaceutical Sciences

Journal of Clinical & Experimental Pharmacology

Author(s): Garland J

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Abstract The variety of genes implicated in cancer induction is extensive but paradoxically all cancer cells behave in an identical and highly predictable fashion. This behaviour is closely correlated with a group of cellular morphological criteria termed Anaplasticity which involves increases/changes in: motility; invasion; replication; nuclear and chromosomal fragmentation; structural degradation; and phenotypic fluidity. Anaplasticity is so predictive it is a universal clinical yardstick for assessment and treatment. To understand this paradox, perceived mechanisms of cancer induction are reviewed and a new proposal made, namely that cancer is a diversion of energy required for structural organisation into maximum energy dissipation (entropy) through increased dynamic activities. This process is driven by oncogenic mutations or a variety of other permanent molecular alterations which re-direct "channels" distributing energy dissipation. These are organised along fractal networks (Fractal Entropy) and are not necessarily structure-dependent. "Oncogenic" alterations of any kind create cumulative effects by permanently stabilising parts of the fractal network, resulting in fractured co-ordination and re-direction of entropy into increased dynamic activity, which is the universal hallmark of cancer. The mechanism of Fractal Entropy employs Chaos and Fractal theories and is illustrated with Mandelbrot figures for fractal distributions and Chaos theory for its influence in creating fractal distributions and their behaviours. The proposal is examined in an in vitro heamatopoietic model (IL3 dependent cells) concerning regulation by growth factors of metabolism, apoptosis, oncogenesis and cell dormancy, and suggests new avenues of multi-disciplinary research. Summary While a genetic basis for cancer is well established, the mechanism(s) by which it is induced remain obscure. Paradoxically, although the spectrum of oncogenic mutations is extremely wide, all cancer cells universally exhibit a characteristic profile regardless of origin, whose progression is extremely predictable: increased proliferation, invasion and migration, loss in architectural integrity (anaplasticity), apoptotic inactivation etc. To understand this discrepancy, an extensive review was performed from the standpoint that since all oncogenes directly or indirectly alter enzyme pathways which control energy management, this may be a critical component of the induction process; alterations in management divert energy away from the construction and maintenance of stable complex structure into dynamic activity such as continuing replication, motility and migration, and architectural fluidity, ie. anaplasticity. This diversion would flow from the laws of thermodynamics which require energy to be dissipated (entropy). The review prompted a model (Fractal Entropy) whereby cellular entropic dissipation follows structure-independent fractal distributions rather than the linearly ordered, sequential pathways currently modelled for signal transduction. "Malignant" behaviour arises from disturbances which bias this fractal network to achieve maximum entropy. Because replication, motility and architectural plasticity all actively dissipate more energy through kinetic activity than by structure-building in which energy becomes "locked in", these routes are preferred eventually generating a universal malignant phenotype independent of the types of mutations and pathways initially affected. A proposed mechanism for the model is based on Chaos and Fractal theories illustrated in the Appendix. These present examples of dynamic fractal behaviour through Mandelbrot figures and of how Chaos theory can initiate and guide distribution of entropy fractals. This proposal accords fully with established physical laws and the most recent research, and reconciles many of the unresolved problems concerning genetic heterogeneity, the universality of malignant cell behaviour, cancer progression, and the well-known, but still unexplained, metabolic Warburg effect. An established in vitro cell model offers evidence for the hypothesis which suggests new directions for multi-disciplinary research into the origin of cancer. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved. This article was published in Crit Rev Oncol Hematol and referenced in Journal of Clinical & Experimental Pharmacology

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