title: Cancer stem cells display extremely large evolvability: alternating plastic and rigid networks as a potential Mechanism: network models, novel therapeutic target strategies, and the contributions of hypoxia, inflammation and cellular senescence.
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".
authors.affiliation: Department of Medical Chemistry, Semmelweis University, P.O. Box 260, H-1444 Budapest 8, Hungary. Electronic address: Csermely@med.semmelweis-univ.hu.
authors.forename: Peter
authors.initials: P
authors.lastname: Csermely
authors.affiliation: Department of Medical Chemistry, Semmelweis University, P.O. Box 260, H-1444 Budapest 8, Hungary.
authors.forename: János
authors.initials: J
authors.lastname: Hódsági
authors.affiliation: Department of Genetics, Eötvös Loránd University, Pázmány P. s. 1C, H-1117 Budapest, Hungary.
authors.forename: Tamás
authors.initials: T
authors.lastname: Korcsmáros
authors.affiliation: Department of Genetics, Eötvös Loránd University, Pázmány P. s. 1C, H-1117 Budapest, Hungary; Semmelweis University, Department of Morphology and Physiology, Faculty of Health Sciences, Vas u. 17, H-1088 Budapest, Hungary.
authors.forename: Dezső
authors.initials: D
authors.lastname: Módos
authors.affiliation: Department of Medical Chemistry, Semmelweis University, P.O. Box 260, H-1444 Budapest 8, Hungary.
authors.forename: Áron R
authors.initials: ÁR
authors.lastname: Perez-Lopez
authors.affiliation: Department of Medical Chemistry, Semmelweis University, P.O. Box 260, H-1444 Budapest 8, Hungary.
authors.forename: Kristóf
authors.initials: K
authors.lastname: Szalay
authors.affiliation: Department of Medical Chemistry, Semmelweis University, P.O. Box 260, H-1444 Budapest 8, Hungary.
authors.forename: Dániel V
authors.initials: DV
authors.lastname: Veres
authors.affiliation: Semmelweis University, Department of Morphology and Physiology, Faculty of Health Sciences, Vas u. 17, H-1088 Budapest, Hungary.
authors.forename: Katalin
authors.initials: K
authors.lastname: Lenti
authors.affiliation: Institute of Applied Mathematics, Academy of Mathematics and Systems Science, Chinese Academy of Sciences, No. 55, Zhongguancun East Road, Beijing 100190, China.
authors.forename: Ling-Yun
authors.initials: LY
authors.lastname: Wu
authors.affiliation: Institute of Applied Mathematics, Academy of Mathematics and Systems Science, Chinese Academy of Sciences, No. 55, Zhongguancun East Road, Beijing 100190, China.
authors.forename: Xiang-Sun
authors.initials: XS
authors.lastname: Zhang
mesh_terms: D015687:Cell Hypoxia / Q000502:physiology*; D002471:Cell Transformation, Neoplastic / Q000473:pathology*; D016922:Cellular Senescence / Q000502:physiology*; D006801:Humans; D007249:Inflammation / Q000473:pathology*; D014411:Neoplastic Stem Cells / Q000473:pathology*
keywords: Anti-cancer therapies; Cancer attractors; Cancer stem cells; Hypoxia; Inflammation; Interactome; Metabolic modeling; Networks; Senescence; Signaling