Cancer Cell Reprogramming: Stem Cell Differentiation Stage Factors and An Agent Based Model to Optimize Cancer Treatment

Biava, Pier Mario; Basevi, Mario; Biggiero, Lucio; Borgonovo, A; Borgonovo, Emanuele; Burigana, Fabio

doi:10.2174/138920111794295783

Cited by 15 publications

(14 citation statements)

References 117 publications

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“…It was confirmed that differences in the expression of genes in embryonic stem cells at different developmental stages results in the production of diverse types and intensity of signaling molecules (45,46). And several signals and pathways of regulation mechanism of induced maturation of tumor cells have been identified (20).…”

Section: Resultsmentioning

confidence: 85%

Developmental Stage-Specific Hepatocytes Induce Maturation of HepG2 Cells by Rebuilding the Regulatory Circuit

Liu

Zong

et al. 2015

Mol Med

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On the basis of their characteristics, we presume that developmental stage-specific hepatocytes should have the ability to induce maturation of hepatoma cells. A regulatory circuit formed by hepatocyte nuclear factor (HNF)-4α, HNF-1α, HNF-6 and the upstream stimulatory factor (USF-1) play a key role in the maturation of embryonic hepatocytes; however, it is unclear whether the regulatory circuit mediates the embryonic induction of hepatoma cell maturation. In this study, 12.5-d to 15.5-d mouse embryonic hepatocytes or their medium were used to coculture or treat HepG2 cells, and the induced maturation was evaluated in vitro and in vivo. In the induced HepG2 cells, the components of the regulatory circuit were detected, their cross-regulation was evaluated and HNF-4α RNA interference was performed. We found that 13.5-d to 14.5-d embryonic hepatocytes could induce HepG2 cell maturation, demonstrated by morphological changes, increased maturation markers and decreased c-Myc and α-fetoprotein (AFP) in vitro. The majority of HepG2 tumors were eliminated by 13.5-d embryonic induction in vivo. All components of the regulatory circuit were upregulated and the binding of HNF-4α, HNF-1α, HNF-6 and USF-1 to their target sites was promoted to rebuild the regulatory circuit in the induced HepG2 cells. Moreover, RNA interference targeting HNF-4α, which is the core of the regulatory circuit, attenuated the induced maturation of HepG2 cells with downregulation of the regulatory circuit. These results revealed that developmental stage-specific hepatocytes could induce the maturation of HepG2 cells by rebuilding the regulatory circuit. is believed to be a controller and marker of mature hepatocytes (27,28). As a downstream target of HNF-4α, HNF-1α is also essential for hepatocyte maturation (29,30). USF-1, which competes with the oncogene c-Myc for the E-box regulatory element, is another downstream target of HNF-4α that plays crucial roles in the maturation and formation of functional hepatocytes (31,32). USF-1 can activate HNF-6, which is another important transcription factor for hepatocyte maturation that has been found to regulate 33). Therefore, HNF-4α, HNF-1α, HNF-6 and USF-1 form a positive feedback loop that drives hepatocyte maturation in liver development ( Figure 1A). Because the transcription factor binding sites are generally believed to scatter within 10 kb upstream of the transcriptional start site (34), the 10-kb gene promoters were all analyzed. On the basis of previous reports (25), the predicted binding sites of HNF-4α HNF-1α, HNF-6 and USF-1 were identified, respectively ( Figure 1B). It remains unknown whether developmental stage-specific hepatocytes rebuild the regulatory circuit to induce the maturation of HepG2 cells.In this study, HepG2 cells were cocultured with mouse embryonic hepatocytes at gestation of 12.5-15.5 d, because the mouse hepatocytes differentiated at 12.5 d, and the liver structure became firmly established between 12 and 15 d of gestation (35)(36)(37). The induced maturation of HepG2 cel...

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Section: Resultsmentioning

confidence: 85%

Developmental Stage-Specific Hepatocytes Induce Maturation of HepG2 Cells by Rebuilding the Regulatory Circuit

Liu

Zong

et al. 2015

Mol Med

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“…The cancer problem has been considered from many different modeling perspectives ranging from the standard mechanistic models [21][22][23][24][25], to applications of population dynamics [26][27][28][29], evolutionary game theory [30][31][32], and models of swarm dynamics [33,34]. However, these methods generally only consider one or two levels of organization in describing the dynamics of the systems they consider, and almost exclusively view the lowest level as giving rise to the higher levels.…”

Section: Information In Biological Systemsmentioning

confidence: 99%

Cancer as a disorder of patterning information: computational and biophysical perspectives on the cancer problem

Moore

Walker

Levin

2017

Converg. Sci. Phys. Oncol.

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TOPICAL REVIEWCancer as a disorder of patterning information: computational and biophysical perspectives on the cancer problem IntroductionCancer is well-recognized not only as an extremely pernicious medical problem, but also as a group of phenomena deeply connected to the fundamental questions of evolution, multicellularity, pattern (disregulation, and the interplay between the genome and the environment [1,2]. Two fundamental paradigms currently divide the field. One is that cancer results from disorders of genetics: cancer cells are fundamentally broken due to genomic mutation or instability, and their clonal progeny form tumors and metastases. This view is sometimes called the SMT, somatic mutation theory [3][4][5]. A competing perspective is that of cancer as a circuit disease-a disorder of the complex biophysical, transcriptional, and epigenetic dynamics that regulate cellular state and the ability of cells to cooperate in vivo [6][7][8]. Under this view (sometimes called the tissue organization field theory or TOFT, [9,10]), cancer is akin to a traffic jam [11]-the problem is not a permanent discrete alteration within a founder cell and all of its clonal descendants, but an undesirable stable attractor in the complex network of controls that normally guides anatomical homeostasis [12].The relative merits of the two models have been discussed extensively [10,[13][14][15][16][17] AbstractThe current paradigm views cancer as arising clonally from a degradation of genetic information in single cells. A complementary perspective, originating at the dawn of modern developmental biology, is that cancer is the result of a system disorder of algorithms that normally orchestrate individual cell activities toward specific anatomical structures and away from tumorigenesis. A view of cancer as a disease of geometry focuses on the pathways that allow cells to cooperate to build and maintain large-scale anatomical patterning. Cancer may result when cells stop maintaining higher-order structures and reduce the boundary of their computational selves to a single-cell level, reverting to a unicellular lifestyle in which the rest of the organism is merely part of the environment at the expense of which all living things survive. While this view has been widely discussed, little progress has been made in providing a quantitative, mechanistic framework within which this perspective's specific and unique implications for treatment strategies can be tested and biomedically exploited. Here, we highlight two recent areas of progress which may facilitate much-needed progress on the cancer problem. First, we review the roles that endogenous bioelectrical networks, operating across many tissues in vivo, play as a medium of information processing in tumor suppression, progression, and reprogramming. Second, we provide a primer to the development of computational theory and tools for quantifying the information and causal control structures in cancer and other complex biological systems. Rigorous mathematical formalisms now exist to...

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“…We may assume that in cancer stem cells the trajectory of multifaceted cross-talk between the genetic/epigenetic environment and cell signaling networks may undergo a deviation from the road map for terminal differentiation. Such hypothesis is supported by decisive experiments performed by Biava and Coworkers [1,[25][26][27][28][29] showing that factors extracted from zebrafish embryos at different stages of embryonic development (embryonic stagedependent factors) are able to induce differentiation and/or apoptosis of human cancer stem cells, bypassing the mutations that are at the origin of the malignant tumor.…”

Section: Cancer Stem Cell Reprogrammingmentioning

confidence: 91%

“…In this regard, it has been shown that the proliferation curves of human tumor cell lines can be slowed down following the exposure to extracts of zebrafish embryos collected during the phases of cell differentiation. On the contrary, there is no significant anti-proliferative effect in the presence of extracts solely yielded from the initial duplicative phase of zebrafish embryogenesis [25][26][27][28][29]. itself ) with consistent sequelae of intracellular events [33,35].…”

Section: Tuning Human Cancer Stem Cell Dynamics With Chemical Agents:mentioning

confidence: 99%

Cancer Stem Cells: Foe or Reprogrammable Cells for Efficient Cancer Therapy?

Ventura¹,

Olivi²,

Cavallini³

et al. 2015

NanoWorld J

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Embryonic development and carcinogenesis share many molecular pathways and regulatory molecules. While the induction of a pluripotent state involves a significant oncogenic risk, as in induced pluripotent stem cells (iPSCs), the embryonic environment in vivo has been shown to suppress tumor development. In this review, we discuss the subtle equilibrium between the nanotopography (niche) of the hosting tissue resident stem cells and their biological dynamics, including the transformation in cancer stem cells. We review consistent findings indicating the potential for modulating the biology of human cancer stem cells by the aid of naturally occurring or synthetic molecules, including developmental stage zebrafish embryo extracts, hyaluronan, butyric acid (BA) and retinoic acid (RA), hyaluronan mixed esters of BA and RA, melatonin, vitamin D3, and endorphin peptides. Within this context, we dissect the multifaceted mechanisms orchestrated by endorphinergic systems, including paracrine cellto-cell communication, as well as the establishment of autocrine and intracrine (intracellular) peptide actions driving transcriptional responses and self-sustaining loops that behave as long-lived signals imparting features characteristic of differentiation, growth regulation and cell memory.Based upon the remarkable action of electromagnetic fields and mechanical vibration on (stem) cell signaling, differentiation, and senescence, we also consider the potential for using these physical energies as a tool to afford a fine tuning of cancer stem cell fate.On the whole, we forecast future deployment of the physical and/or chemical approaches described herein aiming at reprogramming, rather than destroying cancer stem cells, eventually placing cancer therapy within the context of Regenerative Medicine.

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Cancer Cell Reprogramming: Stem Cell Differentiation Stage Factors and An Agent Based Model to Optimize Cancer Treatment

Cited by 15 publications

References 117 publications

Developmental Stage-Specific Hepatocytes Induce Maturation of HepG2 Cells by Rebuilding the Regulatory Circuit

Developmental Stage-Specific Hepatocytes Induce Maturation of HepG2 Cells by Rebuilding the Regulatory Circuit

Cancer as a disorder of patterning information: computational and biophysical perspectives on the cancer problem

Cancer Stem Cells: Foe or Reprogrammable Cells for Efficient Cancer Therapy?

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