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Hydrophobic bile acids, genomic instability, Darwinian selection, and colon carcinogenesis.

Payne CM, Bernstein C, Dvorak K, Bernstein H - Clin Exp Gastroenterol (2008)

Bottom Line: Persistent exposure of colon epithelial cells to hydrophobic bile acids can result in the activation of pro-survival stress-response pathways, and the modulation of numerous genes/proteins associated with chromosome maintenance and mitosis.The multiple mechanisms by which hydrophobic bile acids contribute to genomic instability are discussed, and include oxidative DNA damage, p53 and other mutations, micronuclei formation and aneuploidy.Since bile acids and oxidative stress decrease DNA repair proteins, an increase in DNA damage and increased genomic instability through this mechanism is also described.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Biology and Anatomy, College of Medicine, University of Arizona, Tucson, Arizona, USA.

ABSTRACT
Sporadic colon cancer is caused predominantly by dietary factors. We have selected bile acids as a focus of this review since high levels of hydrophobic bile acids accompany a Western-style diet, and play a key role in colon carcinogenesis. We describe how bile acid-induced stresses cause cell death in susceptible cells, contribute to genomic instability in surviving cells, impose Darwinian selection on survivors and enhance initiation and progression to colon cancer. The most likely major mechanisms by which hydrophobic bile acids induce stresses on cells (DNA damage, endoplasmic reticulum stress, mitochondrial damage) are described. Persistent exposure of colon epithelial cells to hydrophobic bile acids can result in the activation of pro-survival stress-response pathways, and the modulation of numerous genes/proteins associated with chromosome maintenance and mitosis. The multiple mechanisms by which hydrophobic bile acids contribute to genomic instability are discussed, and include oxidative DNA damage, p53 and other mutations, micronuclei formation and aneuploidy. Since bile acids and oxidative stress decrease DNA repair proteins, an increase in DNA damage and increased genomic instability through this mechanism is also described. This review provides a mechanistic explanation for the important link between a Western-style diet and associated increased levels of colon cancer.

No MeSH data available.


Related in: MedlinePlus

Schematic diagram illustrating a probable sequence of events resulting from exposure to high levels of hydrophobic bile acids (HBAs) that accompany a high-fat diet. This exposure leads to HBA-induced generation of ROS/RNS, activation of survival pathways (eg, autophagy, NF-κB), the generation of cells with genomic instability (eg, mutations, aneuploidy) and clonal selection of mutant cells with survival and proliferative advantages. The end results are the production of adenomas that progress to colon cancer. The epithelial cells of the colon of a person on a Western-style (high-fat/low vegetable/low micronutrient) diet are probably in a persistant “war zone” (bombardment with HBA-induced ROS/RNS, presence of food carcinogens, toxins, etc.). Cells in different stages of progression to malignancy are thus persistently receiving damages to their genome, resulting in clones of cells that are selected for survival in the adverse environment of the colon. While cells in the previous population, if receiving excessive DNA damage, underwent cell death altruistically for the overall benefit of the organism, the new clones of cells may behave selfishly. The new clones may acquire resistance to apoptosis and undergo clonal selection on the basis of their survival advantage, even when their DNA is damaged and after their genomes become unstable. This allows progression to adenomas and colon cancer.Abbreviations: AA, arachidonic acid; COX, cyclooxygenase; LOX, lipoxygenase; PLA2, phospholipiase A2; NO, nitric oxide; ROS, reactive oxygen species; RNS, reactive nitrogen species.
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f3-ceg-1-019: Schematic diagram illustrating a probable sequence of events resulting from exposure to high levels of hydrophobic bile acids (HBAs) that accompany a high-fat diet. This exposure leads to HBA-induced generation of ROS/RNS, activation of survival pathways (eg, autophagy, NF-κB), the generation of cells with genomic instability (eg, mutations, aneuploidy) and clonal selection of mutant cells with survival and proliferative advantages. The end results are the production of adenomas that progress to colon cancer. The epithelial cells of the colon of a person on a Western-style (high-fat/low vegetable/low micronutrient) diet are probably in a persistant “war zone” (bombardment with HBA-induced ROS/RNS, presence of food carcinogens, toxins, etc.). Cells in different stages of progression to malignancy are thus persistently receiving damages to their genome, resulting in clones of cells that are selected for survival in the adverse environment of the colon. While cells in the previous population, if receiving excessive DNA damage, underwent cell death altruistically for the overall benefit of the organism, the new clones of cells may behave selfishly. The new clones may acquire resistance to apoptosis and undergo clonal selection on the basis of their survival advantage, even when their DNA is damaged and after their genomes become unstable. This allows progression to adenomas and colon cancer.Abbreviations: AA, arachidonic acid; COX, cyclooxygenase; LOX, lipoxygenase; PLA2, phospholipiase A2; NO, nitric oxide; ROS, reactive oxygen species; RNS, reactive nitrogen species.

Mentions: Although excessive stress will lead to apoptosis, this altruistic act of removing DNA-damaged cells for the survival of the organism becomes largely circumvented in cells with activated survival pathways. In this “war zone”,1 stimulated by the presence of hydrophobic bile acids, mutated epithelial cells may act in a selfish manner,2 like bacterial cells, and Darwinian selection3–10 can come into play at the cellular level. The very stress-response pathways that result in cell survival (eg, activation of nuclear factor-kappa B [NF-κB], autophagy) (Figure 3) can become constitutively upregulated through clonal selection of mutated cells, and can serve to propagate cells even with unrepaired DNA damages and genomic instability. Although it has been known for decades (using animal models of carcinogenesis) that hydrophobic bile acids can promote colon cancer,11–14 the evidence is now convincing that bile acids are also carcinogens.15–17 Evidence that bile acids are carcinogens in human gastrointestinal (GI) cancers has been reviewed by Bernstein and colleagues.15 Proof that hydrophobic bile acids cause mutation in vitro in epithelial cells of the GI tract was provided by the elegant studies of Jenkins and colleagues.16,17 Even though proliferation is essential to cancer development, it is not the high level of proliferation itself that is responsible for cancer. For example, adenocarcinomas are infrequent in the small intestine, although the proliferation rate of epithelial cells at this site is similar to that of the epithelial cells of the colon. The colon may be particularly susceptible to cancer because it contains tissues that are often exposed to unique stresses (eg, high levels of hydrophobic bile acids resulting from anaerobic bacterial metabolism). Since there may be insufficient time for DNA repair in this “war zone”,18 the selection of mutated cells with a proliferative advantage may occur repeatedly. This proliferative advantage may take the form of apoptosis resistance and/or increased cell division.


Hydrophobic bile acids, genomic instability, Darwinian selection, and colon carcinogenesis.

Payne CM, Bernstein C, Dvorak K, Bernstein H - Clin Exp Gastroenterol (2008)

Schematic diagram illustrating a probable sequence of events resulting from exposure to high levels of hydrophobic bile acids (HBAs) that accompany a high-fat diet. This exposure leads to HBA-induced generation of ROS/RNS, activation of survival pathways (eg, autophagy, NF-κB), the generation of cells with genomic instability (eg, mutations, aneuploidy) and clonal selection of mutant cells with survival and proliferative advantages. The end results are the production of adenomas that progress to colon cancer. The epithelial cells of the colon of a person on a Western-style (high-fat/low vegetable/low micronutrient) diet are probably in a persistant “war zone” (bombardment with HBA-induced ROS/RNS, presence of food carcinogens, toxins, etc.). Cells in different stages of progression to malignancy are thus persistently receiving damages to their genome, resulting in clones of cells that are selected for survival in the adverse environment of the colon. While cells in the previous population, if receiving excessive DNA damage, underwent cell death altruistically for the overall benefit of the organism, the new clones of cells may behave selfishly. The new clones may acquire resistance to apoptosis and undergo clonal selection on the basis of their survival advantage, even when their DNA is damaged and after their genomes become unstable. This allows progression to adenomas and colon cancer.Abbreviations: AA, arachidonic acid; COX, cyclooxygenase; LOX, lipoxygenase; PLA2, phospholipiase A2; NO, nitric oxide; ROS, reactive oxygen species; RNS, reactive nitrogen species.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3108627&req=5

f3-ceg-1-019: Schematic diagram illustrating a probable sequence of events resulting from exposure to high levels of hydrophobic bile acids (HBAs) that accompany a high-fat diet. This exposure leads to HBA-induced generation of ROS/RNS, activation of survival pathways (eg, autophagy, NF-κB), the generation of cells with genomic instability (eg, mutations, aneuploidy) and clonal selection of mutant cells with survival and proliferative advantages. The end results are the production of adenomas that progress to colon cancer. The epithelial cells of the colon of a person on a Western-style (high-fat/low vegetable/low micronutrient) diet are probably in a persistant “war zone” (bombardment with HBA-induced ROS/RNS, presence of food carcinogens, toxins, etc.). Cells in different stages of progression to malignancy are thus persistently receiving damages to their genome, resulting in clones of cells that are selected for survival in the adverse environment of the colon. While cells in the previous population, if receiving excessive DNA damage, underwent cell death altruistically for the overall benefit of the organism, the new clones of cells may behave selfishly. The new clones may acquire resistance to apoptosis and undergo clonal selection on the basis of their survival advantage, even when their DNA is damaged and after their genomes become unstable. This allows progression to adenomas and colon cancer.Abbreviations: AA, arachidonic acid; COX, cyclooxygenase; LOX, lipoxygenase; PLA2, phospholipiase A2; NO, nitric oxide; ROS, reactive oxygen species; RNS, reactive nitrogen species.
Mentions: Although excessive stress will lead to apoptosis, this altruistic act of removing DNA-damaged cells for the survival of the organism becomes largely circumvented in cells with activated survival pathways. In this “war zone”,1 stimulated by the presence of hydrophobic bile acids, mutated epithelial cells may act in a selfish manner,2 like bacterial cells, and Darwinian selection3–10 can come into play at the cellular level. The very stress-response pathways that result in cell survival (eg, activation of nuclear factor-kappa B [NF-κB], autophagy) (Figure 3) can become constitutively upregulated through clonal selection of mutated cells, and can serve to propagate cells even with unrepaired DNA damages and genomic instability. Although it has been known for decades (using animal models of carcinogenesis) that hydrophobic bile acids can promote colon cancer,11–14 the evidence is now convincing that bile acids are also carcinogens.15–17 Evidence that bile acids are carcinogens in human gastrointestinal (GI) cancers has been reviewed by Bernstein and colleagues.15 Proof that hydrophobic bile acids cause mutation in vitro in epithelial cells of the GI tract was provided by the elegant studies of Jenkins and colleagues.16,17 Even though proliferation is essential to cancer development, it is not the high level of proliferation itself that is responsible for cancer. For example, adenocarcinomas are infrequent in the small intestine, although the proliferation rate of epithelial cells at this site is similar to that of the epithelial cells of the colon. The colon may be particularly susceptible to cancer because it contains tissues that are often exposed to unique stresses (eg, high levels of hydrophobic bile acids resulting from anaerobic bacterial metabolism). Since there may be insufficient time for DNA repair in this “war zone”,18 the selection of mutated cells with a proliferative advantage may occur repeatedly. This proliferative advantage may take the form of apoptosis resistance and/or increased cell division.

Bottom Line: Persistent exposure of colon epithelial cells to hydrophobic bile acids can result in the activation of pro-survival stress-response pathways, and the modulation of numerous genes/proteins associated with chromosome maintenance and mitosis.The multiple mechanisms by which hydrophobic bile acids contribute to genomic instability are discussed, and include oxidative DNA damage, p53 and other mutations, micronuclei formation and aneuploidy.Since bile acids and oxidative stress decrease DNA repair proteins, an increase in DNA damage and increased genomic instability through this mechanism is also described.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Biology and Anatomy, College of Medicine, University of Arizona, Tucson, Arizona, USA.

ABSTRACT
Sporadic colon cancer is caused predominantly by dietary factors. We have selected bile acids as a focus of this review since high levels of hydrophobic bile acids accompany a Western-style diet, and play a key role in colon carcinogenesis. We describe how bile acid-induced stresses cause cell death in susceptible cells, contribute to genomic instability in surviving cells, impose Darwinian selection on survivors and enhance initiation and progression to colon cancer. The most likely major mechanisms by which hydrophobic bile acids induce stresses on cells (DNA damage, endoplasmic reticulum stress, mitochondrial damage) are described. Persistent exposure of colon epithelial cells to hydrophobic bile acids can result in the activation of pro-survival stress-response pathways, and the modulation of numerous genes/proteins associated with chromosome maintenance and mitosis. The multiple mechanisms by which hydrophobic bile acids contribute to genomic instability are discussed, and include oxidative DNA damage, p53 and other mutations, micronuclei formation and aneuploidy. Since bile acids and oxidative stress decrease DNA repair proteins, an increase in DNA damage and increased genomic instability through this mechanism is also described. This review provides a mechanistic explanation for the important link between a Western-style diet and associated increased levels of colon cancer.

No MeSH data available.


Related in: MedlinePlus