Carcinogenic mechanisms: A critical review and a suggestion that oncogenesis may be adaptive ontogenesis

Nery, Rosane Maria

doi:10.1016/0009-2797(76)90096-x

Cited by 26 publications

(6 citation statements)

References 74 publications

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“…Cellular heterogeneity, and a genomic instability phase during stages of high-grade dysplasia prior to the acquisition of a frankly malignant phenotype, are two well-documented (though so far unexplained) phenomena [33,41]. Similarly well-documented are the picture of a tumor arising in a tissue surrounded by "normal" arrested cells, and the existence of factors involved in organ and tissue regeneration that enhance or are necessary for tumor growth [15,36,42].…”

Section: Origin Of Tumor Cellsmentioning

confidence: 99%

The biological sense of cancer: a hypothesis

Ruggiero

Bustuoabad

2006

Theor Biol Med Model

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Background: Most theories about cancer proposed during the last century share a common denominator: cancer is believed to be a biological nonsense for the organism in which it originates, since cancer cells are believed to be ones evading the rules that control normal cell proliferation and differentiation. In this essay, we have challenged this interpretation on the basis that, throughout the animal kingdom, cancer seems to arise only in injured organs and tissues that display lost or diminished regenerative ability.

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Section: Origin Of Tumor Cellsmentioning

confidence: 99%

The biological sense of cancer: a hypothesis

Ruggiero

Bustuoabad

2006

Theor Biol Med Model

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“…Canonical TGF-β Smad complexes may be more involved in mediating normal physiological homeostasis whereas mixed Smad complexes are preferentially induced during development or in disease processes where locally higher levels of TGF-β are present. Supporting this idea, along with the concept that carcinogenesis often recapitulates development ( Nery 1976 ), mixed Smad signaling complexes are induced in human breast tumor samples and tumor xenografts, with little mixed Smad signaling observed in normal mammary ductal epithelium. This supports the data from cell culture studies where mixed Smad complexes mediated the signaling for TGF-β-induced anchorage-independent growth ( Daly et al 2008 ) and Smad1/5 phosphorylation was necessary for TGF-β-stimulated cell migration ( Bharathy et al 2008 ; Liu et al 2009 ).…”

Section: Discussionmentioning

confidence: 87%

Brightfield Proximity Ligation Assay Reveals Both Canonical and Mixed Transforming Growth Factor-β/Bone Morphogenetic Protein Smad Signaling Complexes in Tissue Sections

Flanders

Heger

Conway

et al. 2014

J Histochem Cytochem.

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Transforming growth factor-β (TGF-β) is an important regulator of cellular homeostasis and disease pathogenesis. Canonical TGF-β signaling occurs through Smad2/3–Smad4 complexes; however, recent in vitro studies suggest that elevated levels of TGF-β may activate a novel mixed Smad complex (Smad2/3-Smad1/5/9), which is required for some of the pro-oncogenic activities of TGF-β. To determine if mixed Smad complexes are evident in vivo, we developed antibodies that can be used with a proximity ligation assay to detect either canonical or mixed Smad complexes in formalin-fixed paraffin-embedded sections. We demonstrate high expression of mixed Smad complexes in the tissues from mice genetically engineered to express high levels of TGF-β1. Mixed Smad complexes were also prominent in 15–16 day gestation mouse embryos and in breast cancer xenografts, suggesting important roles in embryonic development and tumorigenesis. In contrast, mixed Smad complexes were expressed at extremely low levels in normal adult mouse tissue, where canonical complexes were correspondingly higher. We show that this methodology can be used in archival patient samples and tissue microarrays, and we have developed an algorithm to quantitate the brightfield read-out. These methods will allow quantitative analysis of cell type-specific Smad signaling pathways in physiological and pathological processes.

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“…Carcinogenicity could therefore be a special case of a natural phenomenon. Activation of oncogenes, altered chromosomes, and differentiation and redifferentiation could be epiphenomina (Nery, 1976). …”

Section: The Two-stage Modelmentioning

confidence: 97%

Aromatic Amines in Experimental Cancer Research: Tissue-Specific Effects, an Old Problem and New Solutions

Neumann

2007

Critical Reviews in Toxicology

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Carcinogenic aromatic amines usually produce tumors in specific target tissue, such as 2-acetylaminofluorene (AAF) producing liver tumors in rats, in contrast to some other structurally related arylamines. A hypothesis is presented that explains the mode of action in this rat liver model. Genotoxic and nongenotoxic effects work together and make AAF a complete rat liver carcinogen. The cytotoxic, promoting effects are particularly important. N-Hydroxy-2-aminofluorene and 2-nitrosofluorene, two metabolites of AAF, are able to uncouple the mitochondrial respiratory chain. They entertain a redox cycle that removes electrons from the respiratory chain and impairs ATP production. The dose-dependent opening of the mitochondrial permeability transition pore signals the viability of the cell. If the pore is opened to a certain extent, the cell is eliminated by apoptosis. As a consequence, oval cells proliferate, and as this process is overloaded, the liver transforms into a cirrhosis-like situation and thus provides the conditions under which initiated liver cells develop tumors. Such an interpretation is based on assumptions that have been debated for a long time. Some of these often forgotten developments are reviewed in support of the hypothesis, which allows a more comprehensive view of the complex in vivo situation at a time when in vitro models prevail.

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Carcinogenic mechanisms: A critical review and a suggestion that oncogenesis may be adaptive ontogenesis

Cited by 26 publications

References 74 publications

The biological sense of cancer: a hypothesis

The biological sense of cancer: a hypothesis

Brightfield Proximity Ligation Assay Reveals Both Canonical and Mixed Transforming Growth Factor-β/Bone Morphogenetic Protein Smad Signaling Complexes in Tissue Sections

Aromatic Amines in Experimental Cancer Research: Tissue-Specific Effects, an Old Problem and New Solutions

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