Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
10845624 | Seminars in Cancer Biology | 2013 | 8 Pages |
Abstract
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 of cancer stem cells to change the rigidity/plasticity of their networks may be their key hallmark. 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.
Keywords
PDGFRpyruvate kinase M2 isoformTGFBRFBJ murine osteosarcoma viral oncogene homologAnti-cancer therapiesPKM2BRD4IRS1ErbB1MMP2mTORC1BRAFFOXO3aERKFOSnESp53MYCRASTNCPI3KERGRhoACdk6transforming growth factor-β receptorinteractomeCancer developmentinsulin receptor substrate 1Adaptationcyclin-dependent kinase 6extracellular signal regulated protein kinaseSignalingNetworksmatrix metalloproteinase 2Mammalian target of rapamycin complex 1Bromodomain-containing protein 4Epithelial–mesenchymal transitionplatelet-derived growth factor receptorEpidermal growth factor receptor
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Authors
Dávid M. Gyurkó, Dániel V. Veres, DezsÅ Módos, Katalin Lenti, Tamás Korcsmáros, Peter Csermely,