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Mathews J, Chang A(J, Devlin L, Levin M. Cellular signaling pathways as plastic, proto-cognitive systems: Implications for biomedicine. PATTERNS (NEW YORK, N.Y.) 2023; 4:100737. [PMID: 37223267 PMCID: PMC10201306 DOI: 10.1016/j.patter.2023.100737] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 05/25/2023]
Abstract
Many aspects of health and disease are modeled using the abstraction of a "pathway"-a set of protein or other subcellular activities with specified functional linkages between them. This metaphor is a paradigmatic case of a deterministic, mechanistic framework that focuses biomedical intervention strategies on altering the members of this network or the up-/down-regulation links between them-rewiring the molecular hardware. However, protein pathways and transcriptional networks exhibit interesting and unexpected capabilities such as trainability (memory) and information processing in a context-sensitive manner. Specifically, they may be amenable to manipulation via their history of stimuli (equivalent to experiences in behavioral science). If true, this would enable a new class of biomedical interventions that target aspects of the dynamic physiological "software" implemented by pathways and gene-regulatory networks. Here, we briefly review clinical and laboratory data that show how high-level cognitive inputs and mechanistic pathway modulation interact to determine outcomes in vivo. Further, we propose an expanded view of pathways from the perspective of basal cognition and argue that a broader understanding of pathways and how they process contextual information across scales will catalyze progress in many areas of physiology and neurobiology. We argue that this fuller understanding of the functionality and tractability of pathways must go beyond a focus on the mechanistic details of protein and drug structure to encompass their physiological history as well as their embedding within higher levels of organization in the organism, with numerous implications for data science addressing health and disease. Exploiting tools and concepts from behavioral and cognitive sciences to explore a proto-cognitive metaphor for the pathways underlying health and disease is more than a philosophical stance on biochemical processes; at stake is a new roadmap for overcoming the limitations of today's pharmacological strategies and for inferring future therapeutic interventions for a wide range of disease states.
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Affiliation(s)
- Juanita Mathews
- Allen Discovery Center at Tufts University, Medford, MA, USA
| | | | - Liam Devlin
- Allen Discovery Center at Tufts University, Medford, MA, USA
| | - Michael Levin
- Allen Discovery Center at Tufts University, Medford, MA, USA
- Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA, USA
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Mirzayans R, Murray D. What Are the Reasons for Continuing Failures in Cancer Therapy? Are Misleading/Inappropriate Preclinical Assays to Be Blamed? Might Some Modern Therapies Cause More Harm than Benefit? Int J Mol Sci 2022; 23:13217. [PMID: 36362004 PMCID: PMC9655591 DOI: 10.3390/ijms232113217] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Revised: 10/28/2022] [Accepted: 10/28/2022] [Indexed: 07/30/2023] Open
Abstract
Over 50 years of cancer research has resulted in the generation of massive amounts of information, but relatively little progress has been made in the treatment of patients with solid tumors, except for extending their survival for a few months at best. Here, we will briefly discuss some of the reasons for this failure, focusing on the limitations and sometimes misunderstanding of the clinical relevance of preclinical assays that are widely used to identify novel anticancer drugs and treatment strategies (e.g., "synthetic lethality"). These include colony formation, apoptosis (e.g., caspase-3 activation), immunoblotting, and high-content multiwell plate cell-based assays, as well as tumor growth studies in animal models. A major limitation is that such assays are rarely designed to recapitulate the tumor repopulating properties associated with therapy-induced cancer cell dormancy (durable proliferation arrest) reflecting, for example, premature senescence, polyploidy and/or multinucleation. Furthermore, pro-survival properties of apoptotic cancer cells through phoenix rising, failed apoptosis, and/or anastasis (return from the brink of death), as well as cancer immunoediting and the impact of therapeutic agents on interactions between cancer and immune cells are often overlooked in preclinical studies. A brief review of the history of cancer research makes one wonder if modern strategies for treating patients with solid tumors may sometimes cause more harm than benefit.
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3
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Case Studies. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2018; 1069:135-209. [DOI: 10.1007/978-3-319-89354-9_3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
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4
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McDowell G, Rajadurai S, Levin M. From cytoskeletal dynamics to organ asymmetry: a nonlinear, regulative pathway underlies left-right patterning. Philos Trans R Soc Lond B Biol Sci 2017; 371:rstb.2015.0409. [PMID: 27821521 DOI: 10.1098/rstb.2015.0409] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/15/2016] [Indexed: 12/25/2022] Open
Abstract
Consistent left-right (LR) asymmetry is a fundamental aspect of the bodyplan across phyla, and errors of laterality form an important class of human birth defects. Its molecular underpinning was first discovered as a sequential pathway of left- and right-sided gene expression that controlled positioning of the heart and visceral organs. Recent data have revised this picture in two important ways. First, the physical origin of chirality has been identified; cytoskeletal dynamics underlie the asymmetry of single-cell behaviour and patterning of the LR axis. Second, the pathway is not linear: early disruptions that alter the normal sidedness of upstream asymmetric genes do not necessarily induce defects in the laterality of the downstream genes or in organ situs Thus, the LR pathway is a unique example of two fascinating aspects of biology: the interplay of physics and genetics in establishing large-scale anatomy, and regulative (shape-homeostatic) pathways that correct molecular and anatomical errors over time. Here, we review aspects of asymmetry from its intracellular, cytoplasmic origins to the recently uncovered ability of the LR control circuitry to achieve correct gene expression and morphology despite reversals of key 'determinant' genes. We provide novel functional data, in Xenopus laevis, on conserved elements of the cytoskeleton that drive asymmetry, and comparatively analyse it together with previously published results in the field. Our new observations and meta-analysis demonstrate that despite aberrant expression of upstream regulatory genes, embryos can progressively normalize transcriptional cascades and anatomical outcomes. LR patterning can thus serve as a paradigm of how subcellular physics and gene expression cooperate to achieve developmental robustness of a body axis.This article is part of the themed issue 'Provocative questions in left-right asymmetry'.
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Affiliation(s)
- Gary McDowell
- Biology Department, Tufts University, 200 Boston Avenue, Suite 4600, Medford, MA 02155-4243, USA.,Allen Discovery Center, Tufts University, 200 Boston Avenue, Suite 4600, Medford, MA 02155-4243, USA
| | - Suvithan Rajadurai
- Biology Department, Tufts University, 200 Boston Avenue, Suite 4600, Medford, MA 02155-4243, USA.,Allen Discovery Center, Tufts University, 200 Boston Avenue, Suite 4600, Medford, MA 02155-4243, USA
| | - Michael Levin
- Biology Department, Tufts University, 200 Boston Avenue, Suite 4600, Medford, MA 02155-4243, USA .,Allen Discovery Center, Tufts University, 200 Boston Avenue, Suite 4600, Medford, MA 02155-4243, USA
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Rai A, Pradhan P, Nagraj J, Lohitesh K, Chowdhury R, Jalan S. Understanding cancer complexome using networks, spectral graph theory and multilayer framework. Sci Rep 2017; 7:41676. [PMID: 28155908 PMCID: PMC5290734 DOI: 10.1038/srep41676] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2016] [Accepted: 12/15/2016] [Indexed: 02/06/2023] Open
Abstract
Cancer complexome comprises a heterogeneous and multifactorial milieu that varies in cytology, physiology, signaling mechanisms and response to therapy. The combined framework of network theory and spectral graph theory along with the multilayer analysis provides a comprehensive approach to analyze the proteomic data of seven different cancers, namely, breast, oral, ovarian, cervical, lung, colon and prostate. Our analysis demonstrates that the protein-protein interaction networks of the normal and the cancerous tissues associated with the seven cancers have overall similar structural and spectral properties. However, few of these properties implicate unsystematic changes from the normal to the disease networks depicting difference in the interactions and highlighting changes in the complexity of different cancers. Importantly, analysis of common proteins of all the cancer networks reveals few proteins namely the sensors, which not only occupy significant position in all the layers but also have direct involvement in causing cancer. The prediction and analysis of miRNAs targeting these sensor proteins hint towards the possible role of these proteins in tumorigenesis. This novel approach helps in understanding cancer at the fundamental level and provides a clue to develop promising and nascent concept of single drug therapy for multiple diseases as well as personalized medicine.
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Affiliation(s)
- Aparna Rai
- Centre for Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Simrol, Indore, Madhya Pradesh 453552, India
| | - Priodyuti Pradhan
- Complex Systems Lab, Discipline of Physics, Indian Institute of Technology Indore, Simrol, Indore, Madhya Pradesh 453552, India
| | - Jyothi Nagraj
- Department of Biological Sciences, Birla Institute of Technology and Science, Vidya Vihar, Pilani, Rajasthan 333031, India
| | - K. Lohitesh
- Department of Biological Sciences, Birla Institute of Technology and Science, Vidya Vihar, Pilani, Rajasthan 333031, India
| | - Rajdeep Chowdhury
- Department of Biological Sciences, Birla Institute of Technology and Science, Vidya Vihar, Pilani, Rajasthan 333031, India
| | - Sarika Jalan
- Centre for Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Simrol, Indore, Madhya Pradesh 453552, India
- Complex Systems Lab, Discipline of Physics, Indian Institute of Technology Indore, Simrol, Indore, Madhya Pradesh 453552, India
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Increased signaling entropy in cancer requires the scale-free property of protein interaction networks. Sci Rep 2015; 5:9646. [PMID: 25919796 PMCID: PMC4412078 DOI: 10.1038/srep09646] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2014] [Accepted: 03/11/2015] [Indexed: 12/22/2022] Open
Abstract
One of the key characteristics of cancer cells is an increased phenotypic plasticity,
driven by underlying genetic and epigenetic perturbations. However, at a
systems-level it is unclear how these perturbations give rise to the observed
increased plasticity. Elucidating such systems-level principles is key for an
improved understanding of cancer. Recently, it has been shown that signaling
entropy, an overall measure of signaling pathway promiscuity, and computable from
integrating a sample's gene expression profile with a protein interaction
network, correlates with phenotypic plasticity and is increased in cancer compared
to normal tissue. Here we develop a computational framework for studying the effects
of network perturbations on signaling entropy. We demonstrate that the increased
signaling entropy of cancer is driven by two factors: (i) the scale-free (or near
scale-free) topology of the interaction network, and (ii) a subtle positive
correlation between differential gene expression and node connectivity. Indeed, we
show that if protein interaction networks were random graphs, described by Poisson
degree distributions, that cancer would generally not exhibit an increased signaling
entropy. In summary, this work exposes a deep connection between cancer, signaling
entropy and interaction network topology.
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Czarnecka AM, Kornakiewicz A, Lian F, Szczylik C. Future perspectives for mTOR inhibitors in renal cell cancer treatment. Future Oncol 2015; 11:801-17. [DOI: 10.2217/fon.14.303] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
ABSTRACT Everolimus is a mTOR inhibitor that demonstrates antitumor and antiangiogenic activities. In a randomized Phase III trial, patients with metastatic renal cell carcinoma who progressed on sunitinib/sorafenib were treated with everolimus and showed significant improvement in progression-free survival compared with best supportive care. Novel approaches in treatment are expected to ensure less toxic therapies and increase efficacy of everolimus. To provide a new perspective for mTOR inhibitor research and therapy, we discuss renal cell carcinoma cancer stem cells as a potential target for mTOR inhibitors and present new concepts on emerging antiangiogenic therapies. Finally, we point why systems biology approach with reverse molecular engineering may also contribute to the field of drug discovery in renal cell carcinoma.
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Affiliation(s)
- Anna M Czarnecka
- Department of Oncology with Laboratory of Molecular Oncology, Military Institute of Medicine, Szaserow 128, 04-141, Warsaw, Poland
| | - Anna Kornakiewicz
- Department of Oncology with Laboratory of Molecular Oncology, Military Institute of Medicine, Szaserow 128, 04-141, Warsaw, Poland
- Postgraduate School of Molecular Medicine, Medical University of Warsaw, Warsaw, Poland
| | - Fei Lian
- Emory School of Medicine Atlanta, GA 30322, USA
| | - Cezary Szczylik
- Department of Oncology with Laboratory of Molecular Oncology, Military Institute of Medicine, Szaserow 128, 04-141, Warsaw, Poland
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Capone F, Guerriero E, Colonna G, Maio P, Mangia A, Castello G, Costantini S. Cytokinome profile evaluation in patients with hepatitis C virus infection. World J Gastroenterol 2014; 20:9261-9269. [PMID: 25071319 PMCID: PMC4110556 DOI: 10.3748/wjg.v20.i28.9261] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2013] [Revised: 02/20/2014] [Accepted: 05/05/2014] [Indexed: 02/06/2023] Open
Abstract
The ‘‘omics sciences’’ (genomics, transcriptomics, proteomics) are often used to study living organisms as a whole system by evaluating the complex expression patterns of genes, miRNA, proteins, and metabolites. This study aimed, through bioinformatics and systems biology, to decipher the cytokinome profile in the evolution of inflammatory processes leading to cancer. The cytokinome was defined as the totality of cytokines and their interactions in and around biological cells. The system biology approach would provide a better understanding of the complex interaction network of cytokines, especially in cancer patients. Acquired knowledge would enable health providers with tools to evaluate disease onset through progression as well as identifying innovative therapeutic strategies. Understanding the role each cytokine plays in the metabolic network is of great importance. This paper reviews our group’s ‘‘omics’’ work. In particular, it addresses the role cytokines play in liver disease in six different scenarios. The first is the role the cytokines play in chronic inflammatory diseases and cancers. The second is the significance of the cytokinome profile. The third is the role of liver cirrhosis as an inflammatory disease. The fourth is the comparison of cytokine levels evaluated in patients with chronic hepatitis C virus (HCV) or with HCV-related cirrhosis. The fifth is the comparison of cytokine levels evaluated in patients with HCV-related cirrhosis in the presence and absence of type 2 diabetes. And lastly, we present a comparison of cytokine levels evaluated in patients with HCV-related cirrhosis in the presence and absence of hepatocellular carcinoma.
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MESH Headings
- Animals
- Biomarkers/blood
- Carcinoma, Hepatocellular/blood
- Carcinoma, Hepatocellular/immunology
- Carcinoma, Hepatocellular/virology
- Cytokines/blood
- Diabetes Mellitus, Type 2/blood
- Diabetes Mellitus, Type 2/complications
- Diabetes Mellitus, Type 2/immunology
- Hepatitis C, Chronic/blood
- Hepatitis C, Chronic/complications
- Hepatitis C, Chronic/diagnosis
- Hepatitis C, Chronic/immunology
- Humans
- Inflammation Mediators/blood
- Liver Cirrhosis/blood
- Liver Cirrhosis/immunology
- Liver Cirrhosis/virology
- Liver Neoplasms/blood
- Liver Neoplasms/immunology
- Liver Neoplasms/virology
- Prognosis
- Proteomics/methods
- Systems Biology
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Salvatore V, Teti G, Bolzani S, Focaroli S, Durante S, Mazzotti MC, Falconi M. Simulating tumor microenvironment: changes in protein expression in an in vitro co-culture system. Cancer Cell Int 2014; 14:40. [PMID: 24883044 PMCID: PMC4038825 DOI: 10.1186/1475-2867-14-40] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2013] [Accepted: 05/01/2014] [Indexed: 01/01/2023] Open
Abstract
BACKGROUND The role of the microenvironment during the initiation and progression of carcinogenesis is thought to be of critical importance, both for the enhanced understanding of fundamental cancer biology as well as for improving molecular diagnostics and therapeutics. The aim of this study was to establish an in vitro model based on a co-culture of healthy human fibroblasts (HFs) and human osteosarcoma cells (MG-63s) to simulate the microenvironment including tumor and healthy cells. METHODS The HFs and MG-63s were in vitro co-cultured for a period of time ranging from 24 h to 7 days. Cell morphology and organization were studied using phase contrast microscopy while the expression of Human Cartilage Glycoprotein 39 (YKL-40), Vascular Endothelial Growth Factor (VEGF) and Matrix Metalloprotease 1 (MMP1) was investigated by Real Time PCR and Western Blotting. RESULTS The results showed a characteristic disposition of tumor and healthy co-cultured cells in columns which are not visible in tumor and healthy cells grown singularly. The expression of YKL-40, VEGF and MMP1 significantly changed in co-cultured cells compared to HFs and MG-63s separately cultured. CONCLUSIONS We concluded that the tumor microenvironment has an influence on the protein expression of the healthy surrounding tissues and the process of tumorigenicity.
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Affiliation(s)
- Viviana Salvatore
- Department for Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, via Irnerio 48, Bologna 40126, Italy
| | - Gabriella Teti
- Department for Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, via Irnerio 48, Bologna 40126, Italy
| | - Silvia Bolzani
- Department for Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, via Irnerio 48, Bologna 40126, Italy
| | - Stefano Focaroli
- Department for Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, via Irnerio 48, Bologna 40126, Italy
| | - Sandra Durante
- Department for Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, via Irnerio 48, Bologna 40126, Italy
| | - Maria Carla Mazzotti
- Department for Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, via Irnerio 48, Bologna 40126, Italy
| | - Mirella Falconi
- Department for Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, via Irnerio 48, Bologna 40126, Italy
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Guven-Maiorov E, Acuner-Ozbabacan SE, Keskin O, Gursoy A, Nussinov R. Structural pathways of cytokines may illuminate their roles in regulation of cancer development and immunotherapy. Cancers (Basel) 2014; 6:663-83. [PMID: 24670367 PMCID: PMC4074797 DOI: 10.3390/cancers6020663] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2014] [Revised: 03/11/2014] [Accepted: 03/12/2014] [Indexed: 01/06/2023] Open
Abstract
Cytokines are messengers between tissues and the immune system. They play essential roles in cancer initiation, promotion, metastasis, and immunotherapy. Structural pathways of cytokine signaling which contain their interactions can help understand their action in the tumor microenvironment. Here, our aim is to provide an overview of the role of cytokines in tumor development from a structural perspective. Atomic details of protein-protein interactions can help in understanding how an upstream signal is transduced; how higher-order oligomerization modes of proteins can influence their function; how mutations, inhibitors or antagonists can change cellular consequences; why the same protein can lead to distinct outcomes, and which alternative parallel pathways can take over. They also help to design drugs/inhibitors against proteins de novo or by mimicking natural antagonists as in the case of interferon-γ. Since the structural database (PDB) is limited, structural pathways are largely built from a series of predicted binary protein-protein interactions. Below, to illustrate how protein-protein interactions can help illuminate roles played by cytokines, we model some cytokine interaction complexes exploiting a powerful algorithm (PRotein Interactions by Structural Matching-PRISM).
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Affiliation(s)
- Emine Guven-Maiorov
- Center for Computational Biology and Bioinformatics and College of Engineering, Koc University, Rumelifeneri Yolu, 34450 Sariyer Istanbul, Turkey.
| | - Saliha Ece Acuner-Ozbabacan
- Center for Computational Biology and Bioinformatics and College of Engineering, Koc University, Rumelifeneri Yolu, 34450 Sariyer Istanbul, Turkey.
| | - Ozlem Keskin
- Center for Computational Biology and Bioinformatics and College of Engineering, Koc University, Rumelifeneri Yolu, 34450 Sariyer Istanbul, Turkey.
| | - Attila Gursoy
- Center for Computational Biology and Bioinformatics and College of Engineering, Koc University, Rumelifeneri Yolu, 34450 Sariyer Istanbul, Turkey.
| | - Ruth Nussinov
- Cancer and Inflammation Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA.
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11
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Ahmed AA, Zia H, Wagner L. Therapy resistance mechanisms in Ewing's sarcoma family tumors. Cancer Chemother Pharmacol 2014; 73:657-63. [PMID: 24469502 DOI: 10.1007/s00280-014-2392-1] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2013] [Accepted: 01/16/2014] [Indexed: 11/26/2022]
Abstract
Ewing's sarcoma family tumors are aggressive small round cell malignancies that arise in bone or soft tissues in adolescents and young adults. The addition of chemotherapy to local control measures has remarkably improved the survival of patients with localized disease. However, metastatic tumors are often refractory to conventional chemotherapy and irradiation, and the outcome of patients with metastatic or recurrent disease remains dismal. Despite growing understanding of the molecular biology of this tumor and the discovery of new therapeutic targets such as the insulin growth factor-1 receptor, tumor resistance continues to be a formidable challenge. Numerous adaptive mechanisms have been identified which allow tumor cells to escape the cytotoxic effect of chemotherapeutic agents. This review focuses on these mechanisms in an effort to highlight opportunities for more effective disease control.
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Affiliation(s)
- Atif A Ahmed
- Department of Pathology, University of Missouri, Kansas City, MO, USA,
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12
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Csermely P, Hódsági J, Korcsmáros T, Módos D, Perez-Lopez ÁR, Szalay K, Veres DV, Lenti K, Wu LY, Zhang XS. 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. Semin Cancer Biol 2014; 30:42-51. [PMID: 24412105 DOI: 10.1016/j.semcancer.2013.12.004] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2013] [Revised: 12/17/2013] [Accepted: 12/22/2013] [Indexed: 12/13/2022]
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".
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Affiliation(s)
- Peter Csermely
- Department of Medical Chemistry, Semmelweis University, P.O. Box 260, H-1444 Budapest 8, Hungary.
| | - János Hódsági
- Department of Medical Chemistry, Semmelweis University, P.O. Box 260, H-1444 Budapest 8, Hungary
| | - Tamás Korcsmáros
- Department of Genetics, Eötvös Loránd University, Pázmány P. s. 1C, H-1117 Budapest, Hungary
| | - Dezső Módos
- 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
| | - Áron R Perez-Lopez
- Department of Medical Chemistry, Semmelweis University, P.O. Box 260, H-1444 Budapest 8, Hungary
| | - Kristóf Szalay
- Department of Medical Chemistry, Semmelweis University, P.O. Box 260, H-1444 Budapest 8, Hungary
| | - Dániel V Veres
- Department of Medical Chemistry, Semmelweis University, P.O. Box 260, H-1444 Budapest 8, Hungary
| | - Katalin Lenti
- Semmelweis University, Department of Morphology and Physiology, Faculty of Health Sciences, Vas u. 17, H-1088 Budapest, Hungary
| | - Ling-Yun Wu
- Institute of Applied Mathematics, Academy of Mathematics and Systems Science, Chinese Academy of Sciences, No. 55, Zhongguancun East Road, Beijing 100190, China
| | - Xiang-Sun Zhang
- Institute of Applied Mathematics, Academy of Mathematics and Systems Science, Chinese Academy of Sciences, No. 55, Zhongguancun East Road, Beijing 100190, China
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