Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
8362274 | Seminars in Cancer Biology | 2015 | 10 Pages |
Abstract
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 late stages of tumor development. The fluctuating intensity of stress factors, like hypoxia, inflammation and the either cooperative or hostile interactions of tumor inter-cellular networks, all increase the adaptation potential of cancer cells. This may lead to the bypass of cellular senescence, and to the development of cancer stem cells. We propose that the central tenet of cancer stem cell definition lies exactly in the indefinability of cancer stem cells. Actual properties of cancer stem cells depend on the individual “stress-history” of the given tumor. Cancer stem cells are characterized by an extremely large evolvability (i.e. a capacity to generate heritable phenotypic variation), which corresponds well with the defining hallmarks of cancer stem cells: the possession of the capacity to self-renew and to repeatedly re-build the heterogeneous lineages of cancer cells that comprise a tumor in new environments. Cancer stem cells represent a cell population, which is adapted to adapt. We argue that the high evolvability of cancer stem cells is helped by their repeated transitions between plastic (proliferative, symmetrically dividing) and rigid (quiescent, asymmetrically dividing, often more invasive) phenotypes having plastic and rigid networks. Thus, cancer stem cells reverse and replay cancer development multiple times. We describe network models potentially explaining cancer stem cell-like behavior. Finally, we propose novel strategies including combination therapies and multi-target drugs to overcome the Nietzschean dilemma of cancer stem cell targeting: “what does not kill me makes me stronger”.
Keywords
MIRCD34BRAFCD38CDKN2AHRASIL-8TGF-ßSox2Oct4CD133WntNANOGRASZEBE2F transcription factorE2FKLF4leucine-rich repeat-containing G-protein coupled receptor 5KRASCD271PI3KMYD88MYCAnti-cancer therapiesLGR5p53IL-6Bmi1C/EBPNFκBAktinflammationinterleukin 6Interleukin 8Transforming Growth Factor Betainteractomep53 tumor suppressorCancer stem cellsSignalingNetworksTranscription factoroctamer-binding transcription factor 4nuclear factor kappa-BMetabolic modelingMicroRNAHypoxiaCCAAT/enhancer binding proteinSenescencePtenlow affinity nerve growth factor receptor
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Authors
Peter Csermely, János Hódsági, Tamás Korcsmáros, DezsÅ Módos, Áron R. Perez-Lopez, Kristóf Szalay, Dániel V. Veres, Katalin Lenti, Ling-Yun Wu, Xiang-Sun Zhang,