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تسجيل مستخدم جديدAdaptation and learning of molecular networks as a description of cancer development at the systems-level: Potential use in anti-cancer therapies
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There is a widening recognition that cancer cells are products of complex developmental processes. Carcinogenesis and metastasis formation are increasingly described as systems-level, network phenomena. Here we propose that malignant transformation is a two-phase process, where an initial increase of system plasticity is followed by a decrease of plasticity at late stages of carcinogenesis as a model of cellular learning. We describe the hallmarks of increased system plasticity of early, tumor initiating cells, such as increased noise, entropy, conformational and phenotypic plasticity, physical deformability, cell heterogeneity and network rearrangements. Finally, we argue that the large structural changes of molecular networks during cancer development necessitate a rather different targeting strategy in early and late phase of carcinogenesis. Plastic networks of early phase cancer development need a central hit, while rigid networks of late stage primary tumors or established metastases should be attacked by the network influence strategy, such as by edgetic, multi-target, or allo-network drugs. Cancer stem cells need special diagnosis and targeting, since their dormant and rapidly proliferating forms may have more rigid, or more plastic networks, respectively. The extremely high ability to change their rigidity/plasticity may be a key differentiating hallmark of cancer stem cells. The application of early stage-optimized anti-cancer drugs to late-stage patients may be a reason of many failures in anti-cancer therapies. Our hypotheses presented here underlie the need for patient-specific multi-target therapies applying the correct ratio of central hits and network influences -- in an optimized sequence.
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Cancer is increasingly perceived as a systems-level, network phenomenon. The major trend of malignant transformation can be described as a two-phase process, where an initial increase of network plasticity is followed by a decrease of plasticity at l
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The primary activation of the epidermal growth factor receptor (EGFR) has become a prominent target for molecular therapies against several forms of cancer. But despite considerable progress during the last years, many of its aspects remain poorly un
derstood. Experiments on lateral spreading of receptor activity into ligand-free regions challenge the current standard models of EGFR activation. Here, we propose and study a theoretical model, which explains spreading into ligand-free regions without introducing any new, unknown kinetic parameters. The model exhibits bistability of activity, induced by a generic reaction mechanism, which consists of activation via dimerization and deactivation via a Michaelis-Menten reaction. It possesses slow propagating front solutions and faster initial transients. We analyze relevant experiments and find that they are in quantitative accordance with the fast initial modes of spreading, but not with the slow propagating front. We point out that lateral spreading of activity is linked to pathological levels of persistent receptor activity as observed in cancer cells and exemplify uses of this link for the design and quick evaluation of molecular therapies targeting primary activation of EGFR.
The network concept is increasingly used for the description of complex systems. Here we summarize key aspects of the evolvability and robustness of the hierarchical network-set of macromolecules, cells, organisms, and ecosystems. Listing the costs a
nd benefits of cooperation as a necessary behaviour to build this network hierarchy, we outline the major hypothesis of the paper: the emergence of hierarchical complexity needs cooperation leading to the ageing (i.e. gradual deterioration) of the constituent networks. A stable environment develops cooperation leading to over-optimization, and forming an always-old network, which accumulates damage, and dies in an apoptosis-like process. A rapidly changing environment develops competition forming a forever-young network, which may suffer an occasional over-perturbation exhausting system-resources, and causing death in a necrosis-like process. Giving a number of examples we demonstrate how cooperation evokes the gradual accumulation of damage typical to ageing. Finally, we show how various forms of cooperation and consequent ageing emerge as key elements in all major steps of evolution from the formation of protocells to the establishment of the globalized, modern human society.
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