Adult Stem Cell Theory of the Multi-Stage, Multi-Mechanism Theory of Carcinogenesis: Role of Inflammation on the Promotion of Initiated Stem Cells

Trosko, James E.; Tai, Mei Hui

doi:10.1159/000092965

Cited by 74 publications

(72 citation statements)

References 77 publications

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“…However, while Oct3/Oct4 expression in human tumors has previously been reported (60,(83)(84)(85), the expression is typically seen only in a very small fraction of tumor cells (53), possibly cancer stem cells. This can be explained by either of two mechanisms.…”

Section: Discussionmentioning

confidence: 95%

Activated Kras, but Not Hras or Nras, May Initiate Tumors of Endodermal Origin via Stem Cell Expansion

Quinlan

Quatela

Philips

et al. 2008

Molecular and Cellular Biology

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The three closely related human Ras genes, Hras, Nras, and Kras, are all widely expressed, engage a common set of downstream effectors, and can each exhibit oncogenic activity. However, the vast majority of activating Ras mutations in human tumors involve Kras. Moreover, Kras mutations are most frequently seen in tumors of endodermally derived tissues (lung, pancreas, and colon), suggesting that activated Kras may affect an endodermal progenitor to initiate oncogenesis. Using a culture model of retinoic acid (RA)-induced stem cell differentiation to endoderm, we determined that while activated HrasV12 promotes differentiation and growth arrest in these endodermal progenitors, KrasV12 promotes their proliferation. Furthermore, KrasV12-expressing endodermal progenitors fail to differentiate upon RA treatment and continue to proliferate and maintain stem cell characteristics. NrasV12 neither promotes nor prevents differentiation. A structure-function analysis demonstrated that these distinct effects of the Ras isoforms involve their variable C-terminal domains, implicating compartmentalized signaling, and revealed a requirement for several established Ras effectors. These findings indicate that activated Ras isoforms exert profoundly different effects on endodermal progenitors and that mutant Kras may initiate tumorigenesis by expanding a susceptible stem/progenitor cell population. These results potentially explain the high frequency of Kras mutations in tumors of endodermal origin.

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Section: Discussionmentioning

confidence: 95%

Activated Kras, but Not Hras or Nras, May Initiate Tumors of Endodermal Origin via Stem Cell Expansion

Quinlan

Quatela

Philips

et al. 2008

Molecular and Cellular Biology

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“…The promotion process can be brought about by growth, wound healing, inflammatory processes, and non-DNA damaging agents (60). The expansion of an initiated cell seems to be the result of both the mitogenesis of the initiated cell and the inhibition of the apoptosis of these initiated cells (61). Mechanistically, it has been hypothesized that the inhibition of GJIC is responsible for allowing the initiated cell to escape the suppressing effect of surrounding normal cells (62).…”

Section: Multiple Hypothesis Of Carcinogenesismentioning

confidence: 99%

“…Gap junctions, by being involved in the inhibition of cell proliferation, differentiation and apoptosis, can be inhibited by environmental and dietary agents, are involved in the tumor promotion and progression phase of carcinogenesis (64). Both oncogenes and tumor suppressor genes can affect gap junction function (61). Both mutagenic and epigenetic mechanisms can be involved in all phases of the multi-stage process of carcinogenesis.…”

Section: Stem Cell As Targets For the Initiation Process And As The Omentioning

confidence: 99%

Evolution of Energy Metabolism, Stem Cells and Cancer Stem Cells: How the Warburg and Barker Hypotheses Might Be Linked

Trosko

Kang²

2012

Int J Stem Cells

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The evolutionary transition from single cells to the metazoan forced the appearance of adult stem cells and a hypoxic niche, when oxygenation of the environment forced the appearance of oxidative phosphorylation from that of glycolysis. The prevailing paradigm in the cancer field is that cancers start from the "immortalization" or "re-programming" of a normal, differentiated cell with many mitochondria, that metabolize via oxidative phosphorylation. This paradigm has been challenged with one that assumes that the target cell for carcinogenesis is the normal, immortal adult stem cell, with few mitochondria. This adult organ-specific stem cell is blocked from "mortalizing" or from "programming" to be terminally differentiated. Two hypotheses have been offered to explain cancers, namely, the "stem cell theory" and the "de-differentiation" or "re-programming" theory. This Commentary postulates that the paleochemistry of the oceans, which, initially, provided conditions for life's energy to arise via glycolysis, changed to oxidative phosphorylation for life's processes. In doing so, stem cells evolved, within hypoxic niches, to protect the species germinal and somatic genomes. This Commentary provides support for the "stem cell theory", in that cancer cells, which, unlike differentiated cells, have few mitochondria and metabolize via glycolysis. The major argument against the "de-differentiation theory" is that, if re-programming of a differentiated cell to an "induced pluri-potent stem cell" happened in an adult, teratomas, rather than carcinomas, should be the result.

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“…Most likely, they should be classified as "carcinogenic-indirect endogenous promoters" 61 and are probably working as inflammatory agents. [62][63][64] N. Natural endogenous chemicals, which work by different biochemical mechanisms, can be tumor promoters.…”

Section: J the Epigenetic Clonal Expansion Of Initiated Cells By Epimentioning

confidence: 99%

Reflections on the use of 10 IARC carcinogenic characteristics for an objective approach to identifying and organizing results from certain mechanistic studies

Trosko

2017

Toxicology Research and Application

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To find a scientifically based method for evaluating mechanistic data related to risks to human beings, a new protocol for identifying, organizing, and summarizing mechanistic data for decision-making on cancer hazard identification was proposed by the International Agency for Research on Cancer and by an international working group of multidisciplinary experts. This Commentary examined the 10 key carcinogens' characteristics proposed in the context of several paradigms assumed in the using of these 10 characteristics. These characteristics were assumed to represent a "carcinogen's" mechanism of action but what was ignored were characteristics of the mechanisms of the "initiation," "promotion," and "progression" carcinogenic process. Challenges were made to the interpretation of genotoxicity data as well as from concepts and findings related to the promotion phase and the role of adult human stem cells. Reliance of interpretation of "genotoxicity" data (molecular-DNA lesions in DNA; induction of free radicals/oxidative stress markers; phenotypic surrogates of gene mutations), as well as from lesions in genomic versus mitochondrial DNA, or in the target cells for the carcinogenic process in either in vitro cultures or in vivo tissues, makes this "objective" use of the data questionable. A challenge to the "dedifferentiation" hypothesis of cancer was made. Because of an agent being misclassified as "genotoxic"-rather than an "epigenetic"-agent (which works by threshold levels; can be blocked; and must be present at critical times during development and at regular, sustained chronic exposures) could lead to unwise policy decisions.

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Adult Stem Cell Theory of the Multi-Stage, Multi-Mechanism Theory of Carcinogenesis: Role of Inflammation on the Promotion of Initiated Stem Cells

Cited by 74 publications

References 77 publications

Activated Kras, but Not Hras or Nras, May Initiate Tumors of Endodermal Origin via Stem Cell Expansion

Activated Kras, but Not Hras or Nras, May Initiate Tumors of Endodermal Origin via Stem Cell Expansion

Evolution of Energy Metabolism, Stem Cells and Cancer Stem Cells: How the Warburg and Barker Hypotheses Might Be Linked

Reflections on the use of 10 IARC carcinogenic characteristics for an objective approach to identifying and organizing results from certain mechanistic studies

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