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  1. Article ; Online: Induction of iPS cells and of cancer stem cells: the stem cell or reprogramming hypothesis of cancer?

    Trosko, James E

    Anatomical record (Hoboken, N.J. : 2007)

    2014  Volume 297, Issue 1, Page(s) 161–173

    Abstract: This article as designed to examine whether the "stoichiometric" or "elite models" of the origin of the "induced pluripotent stem" (iPS) cells fits some experiment facts from the developmental biology of adult stem cells and from the field of cancer ... ...

    Abstract This article as designed to examine whether the "stoichiometric" or "elite models" of the origin of the "induced pluripotent stem" (iPS) cells fits some experiment facts from the developmental biology of adult stem cells and from the field of cancer research. In brief, since the evidence presented to support the stoichiometric model failed to recognize the factual existence of adult organ specific stem cells, the model has not been rigorously tested. In addition, the demonstration of a subset of cells (MUSE cells) in normal primary in vitro cultures of human fibroblasts (the usual source of iPS cells) seems to be the origin of the iPS cells. Moreover, from the field of carcinogenesis, the "stem cell" versus "de-differentiation" or "reprogramming" hypotheses were examined. Again, using the role of glycolysis, known to be associated with the Warburg effect in cancer cells, a list of experiments showing that (a) normal stem cells, which have few mitochondria, metabolize via glycolysis; (b) the stem cells are targets for "initiation" or "immortalization" or the blockage of differentiation and apoptosis of the stem cells by "immortalizing viruses"; (c) Lactate dehydrogenase A (LDHA), when expressed, is associated with glycolysis and therefore, must be expressed in normal adult stem cells, as well as in cancer cells; and (d) p53, depleted or rendered dysfunctional by SV40 Large T antigen, is associated with the reduction of mitochondrial function and mass and is associated with the Warburg effect. Together, these observations from the iPS and "cancer stem cell" fields support the idea that both iPS cells and cancer stem cell are derived from adult organ-specific stem cells that do not restore or switch their metabolism of glucose from oxidative metabolism to glycolysis but, rather, in both cases, the adult stem cell, which metabolizes by glycolysis, is prevented from differentiation or from metabolizing by oxidative phosphorylation.
    MeSH term(s) Adult ; Adult Stem Cells/cytology ; Adult Stem Cells/physiology ; Cell Differentiation ; Cellular Reprogramming ; Humans ; Induced Pluripotent Stem Cells/cytology ; Induced Pluripotent Stem Cells/physiology ; Neoplasms/pathology ; Neoplastic Stem Cells/pathology ; Oxidative Phosphorylation
    Language English
    Publishing date 2014-01
    Publishing country United States
    Document type Journal Article ; Review
    ZDB-ID 2269667-2
    ISSN 1932-8494 ; 1932-8486
    ISSN (online) 1932-8494
    ISSN 1932-8486
    DOI 10.1002/ar.22793
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: Review paper: cancer stem cells and cancer nonstem cells: from adult stem cells or from reprogramming of differentiated somatic cells.

    Trosko, J E

    Veterinary pathology

    2009  Volume 46, Issue 2, Page(s) 176–193

    Abstract: Two opposing hypotheses of the origin of cancer have existed for many decades. One hypothesis postulates that the adult stem cell is needed to initiate the carcinogenic process, whereas the other claims a somatic differentiated cell can dedifferentiate ... ...

    Abstract Two opposing hypotheses of the origin of cancer have existed for many decades. One hypothesis postulates that the adult stem cell is needed to initiate the carcinogenic process, whereas the other claims a somatic differentiated cell can dedifferentiate or be reprogrammed to regain properties associated with cancer cells. Recent reemergence of the cancer stem cell hypothesis and the isolation of presumptive cancer stem cells from many types of cancer have forced a reexamination of these 2 hypotheses of the origin of cancer. In addition, normal embryonic and adult stem cells have now been isolated and partially characterized. Furthermore, the demonstration of embryonic-like stem cells, being isolated from adult-differentiated skin fibroblast cells of mice, monkey, and human beings, provides a newer opportunity to determine which of these 2 hypotheses might explain the cell type for initiating the carcinogenic process. The goal of this review is to integrate these recent findings, concerning the isolation of normal and cancer stem cells, with several of the classical concepts of carcinogenesis (initiation/promotion/progression; mutation/epigenetic; stem cell theory/dedifferentiation hypotheses; oncogene-tumor suppressor theory). Although the weight of the evidence in this review seems to support the stem cell hypothesis, only future studies, probably using comparative animal and human oncologic studies, will determine if targeting the cancer stem cell, with individualized medical approaches, will improve cancer prevention and therapy.
    MeSH term(s) Adult Stem Cells/pathology ; Animals ; Cell Differentiation ; Humans ; Mice ; Neoplasms/pathology
    Language English
    Publishing date 2009-03
    Publishing country United States
    Document type Journal Article ; Review
    ZDB-ID 188012-3
    ISSN 1544-2217 ; 0300-9858
    ISSN (online) 1544-2217
    ISSN 0300-9858
    DOI 10.1354/vp.46-2-176
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Role of diet and nutrition on the alteration of the quality and quantity of stem cells in human aging and the diseases of aging.

    Trosko, J E

    Current pharmaceutical design

    2006  Volume 14, Issue 26, Page(s) 2707–2718

    Abstract: An integrative synthesis of concepts and an explosion of experimental and epidemiological findings allow new insights as to how the interactions of genetic, environmental, dietary, cultural (social, psychological, economic) factors can influence the ... ...

    Abstract An integrative synthesis of concepts and an explosion of experimental and epidemiological findings allow new insights as to how the interactions of genetic, environmental, dietary, cultural (social, psychological, economic) factors can influence the aging and diseases of aging processes. Although the net effect of the best dietary maintenance of homeostatic control of cell proliferation, cell differentiation and apoptosis, systems breakdown of the human being and death will inevitably be the ultimate end result. Reduction of the quantity of the stem cell pool in any tissue will affect the "aging" of that organ. This, in turn, will affect the homeostatic maintenance of the organ systems of the human. Clearly, not all organs of the body age uniformly. The quality of the stem cells in any organ, depending on circumstances, can contribute to various disease pathogeneses. In the case where the quality of the stem cells is altered in utero or early postnatal development by some mutagenic mechanism that could lead to the initiation step of carcinogenesis, then the individual can, to some degree, control the fate of those prenatally and early postnatally-derived initiated stem cells by choosing those environmentally and dietary factors that either enhance or prevent the clonal expansion of these initiated stem cells during the promotion phase of carcinogenesis. This might explain the Barker hypothesis which suggests that prenatal and early postnatal exposures to toxic agents can lead to diseases later in life.
    MeSH term(s) Aged ; Aging ; Animals ; Apoptosis/physiology ; Cell Differentiation/physiology ; Cell Proliferation ; Diet ; Female ; Homeostasis/physiology ; Humans ; Neoplasms/etiology ; Neoplasms/prevention & control ; Nutritional Status/physiology ; Pregnancy ; Prenatal Exposure Delayed Effects/etiology ; Prenatal Exposure Delayed Effects/physiopathology ; Stem Cells/metabolism
    Language English
    Publishing date 2006-01-23
    Publishing country United Arab Emirates
    Document type Journal Article ; Review
    ZDB-ID 1304236-1
    ISSN 1873-4286 ; 1381-6128
    ISSN (online) 1873-4286
    ISSN 1381-6128
    DOI 10.2174/138161208786264106
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article: The role of stem cells and gap junctions as targets for cancer chemoprevention and chemotherapy.

    Trosko, J E

    Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie

    2006  Volume 59 Suppl 2, Page(s) S326–31

    Abstract: Since carcinogenesis is a multi-stage, multi-mechanism process, involving mutagenic, cell death and epigenetic mechanisms, during the "initiation/promotion/and progression" phases, chemoprevention must be based on understanding the mechanism(s) of each ... ...

    Abstract Since carcinogenesis is a multi-stage, multi-mechanism process, involving mutagenic, cell death and epigenetic mechanisms, during the "initiation/promotion/and progression" phases, chemoprevention must be based on understanding the mechanism(s) of each phase. Prevention of each phase could reduce the risk to cancer. Because reducing the initiation phase to a zero level is impossible, the most effective intervention would be at the promotion phase. Assuming the "target" cells for carcinogenesis are the pluri-potent stem cells and their early progenitor or transit cells, chemoprevention strategies for inhibiting the promotion of these two types of pre-malignant "initiated" cells will require different agents. A hypothesis will be proposed that involves stem cells, which lack gap junctional intercellular communication (GJIC-) or their early progenitor daughter cells, which express GJIC+ and are partially-differentiated, if initiated, will be promoted by agents that either inhibit secreted negative growth regulators or by inhibitors of GJIC. Chemopreventing agents to each of these two types of initiated cells must have different mechanisms of action. Assuming stem cells are target cells for carcinogenesis, an alternative method of chemoprevention would be to reduce the stem cell pool. Anti-tumor promoter chemopreventive agents, such as green tea components, resveratrol, caffeic acid phenethylene ester, that either up-regulate GJIC in stem cells or prevent the down regulation of GJIC by tumor promoters in early progenitor cells, will be provided. Human pluri-potent stem cell systems, that can be induced to form 3-dimensional "organoid" structures, will be discussed as a more realistic model system to screen for relevant chemopreventive agents.
    MeSH term(s) Animals ; Anticarcinogenic Agents/pharmacology ; Antineoplastic Agents/pharmacology ; Cell Communication/drug effects ; Gap Junctions/physiology ; Humans ; Neoplasms/drug therapy ; Neoplasms/physiopathology ; Neoplasms/prevention & control ; Stem Cells/physiology
    Chemical Substances Anticarcinogenic Agents ; Antineoplastic Agents
    Language English
    Publishing date 2006-02-13
    Publishing country France
    Document type Journal Article ; Review
    ZDB-ID 392415-4
    ISSN 1950-6007 ; 0753-3322 ; 0300-0893
    ISSN (online) 1950-6007
    ISSN 0753-3322 ; 0300-0893
    DOI 10.1016/s0753-3322(05)80065-4
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article: Review Paper: Cancer Stem Cells and Cancer Nonstem Cells: From Adult Stem Cells or from Reprogramming of Differentiated Somatic Cells

    Trosko, J. E

    Veterinary pathology. , v. 46, no. 2

    2009  

    Abstract: Two opposing hypotheses of the origin of cancer have existed for many decades. One hypothesis postulates that the adult stem cell is needed to initiate the carcinogenic process, whereas the other claims a somatic differentiated cell can dedifferentiate ... ...

    Abstract Two opposing hypotheses of the origin of cancer have existed for many decades. One hypothesis postulates that the adult stem cell is needed to initiate the carcinogenic process, whereas the other claims a somatic differentiated cell can dedifferentiate or be reprogrammed to regain properties associated with cancer cells. Recent reemergence of the cancer stem cell hypothesis and the isolation of presumptive cancer stem cells from many types of cancer have forced a reexamination of these 2 hypotheses of the origin of cancer. In addition, normal embryonic and adult stem cells have now been isolated and partially characterized. Furthermore, the demonstration of embryonic-like stem cells, being isolated from adult-differentiated skin fibroblast cells of mice, monkey, and human beings, provides a newer opportunity to determine which of these 2 hypotheses might explain the cell type for initiating the carcinogenic process. The goal of this review is to integrate these recent findings, concerning the isolation of normal and cancer stem cells, with several of the classical concepts of carcinogenesis (initiation/promotion/progression; mutation/epigenetic; stem cell theory/dedifferentiation hypotheses; oncogenetumor suppressor theory). Although the weight of the evidence in this review seems to support the stem cell hypothesis, only future studies, probably using comparative animal and human oncologic studies, will determine if targeting the cancer stem cell, with individualized medical approaches, will improve cancer prevention and therapy.
    Keywords carcinogenesis ; cell dedifferentiation ; cell differentiation ; fibroblasts ; gene expression ; genes ; humans ; mice ; monkeys ; neoplasms ; somatic cells ; stem cells
    Language English
    Dates of publication 2009-03
    Size p. 176-193.
    Publishing place SAGE Publications
    Document type Article
    ZDB-ID 188012-3
    ISSN 1544-2217 ; 0300-9858
    ISSN (online) 1544-2217
    ISSN 0300-9858
    DOI 10.1354/vp.46-2-176
    Database NAL-Catalogue (AGRICOLA)

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  6. Article: From bacteria to humans: lessons learned from a reductionist's view of ultraviolet light-induced DNA lesions.

    Trosko, J E

    Environmental and molecular mutagenesis

    2003  Volume 38, Issue 2-3, Page(s) 118–121

    Abstract: What follows is a personal remembrance of how Dr. Richard Setlow influenced me as a young postdoctoral fellow at Oak Ridge National laboratory between 1963 and 1966. The narrative tries to place my "maturation" as a young, inexperienced scientist in the ... ...

    Abstract What follows is a personal remembrance of how Dr. Richard Setlow influenced me as a young postdoctoral fellow at Oak Ridge National laboratory between 1963 and 1966. The narrative tries to place my "maturation" as a young, inexperienced scientist in the context of the cultural upheaval caused by the Vietnam war, of a Northerner facing a "culture-shock" living in the South and in a revolution in molecular and radiation biology taking place at Oak Ridge National Laboratory at that time. The unique historic juxtaposition of Dr. Setlow's contribution of the discovery of UV-induced pyrimidine dimers in bacterial DNA, being potentially the molecular lesion responsible for cell killing and mutagenesis, occurring as I was at Oak Ridge, and the wonderful working relationship I had with William Carrier, his technician, led to our discovery with James Regan that normal human cells repaired these lesion from their DNA. Amazingly, because of Dr. Setlow's challenge to me about my thoughts of the implications of his findings in bacteria, the chance visit to Oak Ridge National Laboratory by Dr. James Cleaver and my background as a human geneticist provided me the extraordinary opportunity to carry out a collaboration to test if human cancer prone syndromes might be deficient in the repair of these UV-induced DNA lesions. With our finding that the direct demonstration of a lack of repair of UV-induced pyrimidine dimers in cells from the skin cancer prone syndrome, xeroderma pigmentosum, opened up a new paradigm for the understanding of the molecular mechanism of carcinogenesis of both radiation and chemical carcinogenesis. From this investigator's vantage point in the history of the understanding of carcinogenesis, which has led us to the present point of "oncogenes" and "tumor suppressor genes", the old adage by Newton, "I only saw further because I stood on the shoulder of giants", is so applicable here. Dr. Setlow's shoulders were indeed among those of all of us that have made some small contribution in trying to understand this extremely complex process of human carcinogenesis.
    MeSH term(s) Bacteria/genetics ; Bacteria/radiation effects ; DNA Damage/radiation effects ; DNA Repair ; DNA, Bacterial/genetics ; DNA, Bacterial/radiation effects ; History, 20th Century ; Humans ; Mentors/history ; Radiobiology/history ; Ultraviolet Rays ; United States
    Chemical Substances DNA, Bacterial
    Language English
    Publishing date 2003-03-07
    Publishing country United States
    Document type Autobiography ; Biography ; Historical Article ; Journal Article
    ZDB-ID 639145-x
    ISSN 1098-2280 ; 0893-6692
    ISSN (online) 1098-2280
    ISSN 0893-6692
    DOI 10.1002/em.1061
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: Categorizing the characteristics of human carcinogens: a need for specificity.

    Smith, Carr J / Perfetti, Thomas A / Hayes, A Wallace / Berry, Sir Colin / Trosko, James E / King, Judy A / Goodman, Jay I / Begley, C Glenn / Dayan, Anthony

    Archives of toxicology

    2021  Volume 95, Issue 8, Page(s) 2883–2889

    Abstract: The International Agency for Research on Cancer (IARC) has recently proposed employing "ten key characteristics of human carcinogens" (TKCs) to determine the potential of agents for harmful effects. The TKCs seem likely to confuse the unsatisfactory ... ...

    Abstract The International Agency for Research on Cancer (IARC) has recently proposed employing "ten key characteristics of human carcinogens" (TKCs) to determine the potential of agents for harmful effects. The TKCs seem likely to confuse the unsatisfactory correlation from testing regimes that have ignored the differences evident when cellular changes are compared in short and long-lived species, with their very different stem cell and somatic cell phylogenies. The proposed characteristics are so broad that their use will lead to an increase in the current unacceptably high rate of false positives. It could be an informative experiment to take well-established approved therapeutics with well-known human safety profiles and test them against this new TKC paradigm. Cancers are initiated and driven by heritable and transient changes in gene expression, expand clonally, and progress via additional associated acquired mutations and epigenetic alterations that provide cells with an evolutionary advantage. The genotoxicity testing protocols currently employed and required by regulation, emphasize testing for the mutational potential of the test agent. Two-year, chronic rodent cancer bioassays are intended to test for the entire spectrum of carcinogenic transformation. The use of cytotoxic doses causing increased, sustained cell proliferation that facilitates accumulated genetic damage leads to a high false-positive rate of tumor induction. Current cancer hazard assessment protocols and weight-of-the-evidence analysis of agent-specific cancer risk align poorly with the pathogenesis of human carcinoma and so need modernization and improvement in ways suggested here.
    MeSH term(s) Animals ; Carcinogenesis/chemically induced ; Carcinogenicity Tests/methods ; Carcinogens/administration & dosage ; Carcinogens/toxicity ; Cell Proliferation/drug effects ; Dose-Response Relationship, Drug ; Humans ; Mutagenicity Tests/methods ; Neoplasms/chemically induced ; Risk Assessment ; Rodentia ; Sensitivity and Specificity
    Chemical Substances Carcinogens
    Language English
    Publishing date 2021-06-20
    Publishing country Germany
    Document type Editorial
    ZDB-ID 124992-7
    ISSN 1432-0738 ; 0340-5761
    ISSN (online) 1432-0738
    ISSN 0340-5761
    DOI 10.1007/s00204-021-03109-w
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article: Bioethics: a philosophical basis for moral decisions.

    Trosko, J E

    Taiwan yi xue ren wen xue kan

    2001  Volume 2, Issue 1-2, Page(s) 29–33

    MeSH term(s) Bioethics ; Ecosystem ; Human Characteristics ; Humans ; Philosophy ; Science
    Language English
    Publishing date 2001-10
    Publishing country China (Republic : 1949- )
    Document type Journal Article
    ISSN 1606-5727
    ISSN 1606-5727
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article: EFFECT ON GENETIC DAMAGE OF POSTTREATMENTS GIVEN X-RAYED DROSOPHILA MALES.

    TROSKO, J E

    Genetics

    2001  Volume 49, Page(s) 401–409

    MeSH term(s) Animals ; Cold Temperature ; Drosophila ; Radiation Genetics ; Research
    Language English
    Publishing date 2001-02-08
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2167-2
    ISSN 1943-2631 ; 0016-6731
    ISSN (online) 1943-2631
    ISSN 0016-6731
    DOI 10.1093/genetics/49.3.401
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article: Commentary: is the concept of "tumor promotion" a useful paradigm?

    Trosko, J E

    Molecular carcinogenesis

    2001  Volume 30, Issue 3, Page(s) 131–137

    Abstract: ... to explain the unique characteristics of each phase (e.g., initiation, being irreversible, was ascribed ... of many in vitro assays used to characterize mutagens, by integrating other theories of carcinogenesis (i.e ...

    Abstract Since the demonstration of the multistage nature of carcinogenesis in experimental work on mouse skin carcinogenesis (and subsequently on various other organ systems in other organisms), the concepts of "initiation", "promotion", and "progression" were operationally generated from empiric data. Because these early observations and concepts had no mechanistic explanations, various hypotheses have been generated to explain the unique characteristics of each phase (e.g., initiation, being irreversible, was ascribed as the result of DNA damage leading to mutagenesis; promotion, being interruptible or reversible, was believed to be caused by epigenetic mechanisms; progression, also being irreversible, was believed to be caused by genetic instability that led to mutagenic and epigenetic changes). In addition, many of the molecular, biochemical, and cellular experiments designed to investigate the mechanistic bases of these phases used technologies that did not always lead to unequivocal interpretations, and because "real-life" carcinogenesis does not mimic controlled experimental conditions of the initiation/promotion/progression experiments, many investigators believe that these concepts have lost their usefulness. In this commentary, I explain some of the confusion concerning the concept of promotion and suggest that, by understanding the limitations of many in vitro assays used to characterize mutagens, by integrating other theories of carcinogenesis (i.e., stem cell theory), and by recognizing the role of epigenetic agents, specifically, modulated gap-junctional intercellular communication, the concept of promotion can provide valuable insights into the carcinogenic process. Mol. Carcinog. 30:131--137, 2001.
    MeSH term(s) Animals ; Carcinogens/pharmacology ; Cell Communication ; Cell Transformation, Neoplastic ; Clone Cells ; Drug Screening Assays, Antitumor ; Gap Junctions/physiology ; Humans ; Models, Biological ; Mutagens/pharmacology ; Oligonucleotide Array Sequence Analysis ; Stem Cells/physiology
    Chemical Substances Carcinogens ; Mutagens
    Language English
    Publishing date 2001-03
    Publishing country United States
    Document type Journal Article ; Research Support, U.S. Gov't, P.H.S. ; Review
    ZDB-ID 1004029-8
    ISSN 1098-2744 ; 0899-1987
    ISSN (online) 1098-2744
    ISSN 0899-1987
    Database MEDical Literature Analysis and Retrieval System OnLINE

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