Limits...
EMAST is a Form of Microsatellite Instability That is Initiated by Inflammation and Modulates Colorectal Cancer Progression.

Carethers JM, Koi M, Tseng-Rogenski SS - Genes (Basel) (2015)

Bottom Line: MSI-H is highly correlated with loss of MMR protein expression, is commonly diploid, is often located in the right side of the colon, prognosticates good patient outcome, and predicts poor efficacy with 5-fluorouracil treatment.Elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) is another form of MSI at tetranucleotide repeats that has been observed in multiple cancers, but its etiology and clinical relevance to patient care has only been recently illuminated.Tumor hypoxia may also be a contributor.

View Article: PubMed Central - PubMed

Affiliation: Division of Gastroenterology, Department of Internal Medicine, University of Michigan, 3101 Taubman Center, 1500 East Medical Center Drive, Ann Arbor, MI 48109, USA. jcarethe@umich.edu.

ABSTRACT
DNA mismatch repair (MMR) function is critical for correcting errors coincident with polymerase-driven DNA replication, and its proteins are frequent targets for inactivation (germline or somatic), generating a hypermutable tumor that drives cancer progression. The biomarker for defective DNA MMR is microsatellite instability-high (MSI-H), observed in ~15% of colorectal cancers, and defined by mono- and dinucleotide microsatellite frameshift mutations. MSI-H is highly correlated with loss of MMR protein expression, is commonly diploid, is often located in the right side of the colon, prognosticates good patient outcome, and predicts poor efficacy with 5-fluorouracil treatment. Elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) is another form of MSI at tetranucleotide repeats that has been observed in multiple cancers, but its etiology and clinical relevance to patient care has only been recently illuminated. Specifically, EMAST is an acquired somatic defect observed in up to 60% of colorectal cancers and caused by unique dysfunction of the DNA MMR protein MSH3 (and its DNA MMR complex MutSβ, a heterodimer of MSH2-MSH3), and in particular a loss-of-function phenotype due to a reversible shift from its normal nuclear location into the cytosol in response to oxidative stress and the pro-inflammatory cytokine interleukin-6. Tumor hypoxia may also be a contributor. Patients with EMAST colorectal cancers show diminished prognosis compared to patients without the presence of EMAST in their cancer. In addition to defective DNA MMR recognized by tetranucleotide (and di- and tri-nucleotide) frameshifts, loss of MSH3 also contributes to homologous recombination-mediated repair of DNA double stranded breaks, indicating the MSH3 dysfunction is a complex defect for cancer cells that generates not only EMAST but also may contribute to chromosomal instability and aneuploidy. Areas for future investigation for this most common DNA MMR defect among colorectal cancers include relationships between EMAST and chemotherapy response, patient outcome with aneuploid changes in colorectal cancers, target gene mutation analysis, and mechanisms related to inflammation-induced compartmentalization and inactivation for MSH3.

No MeSH data available.


Related in: MedlinePlus

A model for modulation of the pathogenesis of colorectal cancer by EMAST. After the tumor has initiated, inflammation can modify the DNA repair function within the tumor through cytokine signaling, hypoxia, and oxidative stress. Evidence supports that Interleukin-6 can shift MSH3 protein from its nuclear locale to the cytosol, allowing accumulation of mutations and double strand breaks. It is believed that these genetic changes modify the tumor behavior, as patients with EMAST cancers present with advanced stage and are more likely to have metastasis.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4488660&req=5

genes-06-00185-f003: A model for modulation of the pathogenesis of colorectal cancer by EMAST. After the tumor has initiated, inflammation can modify the DNA repair function within the tumor through cytokine signaling, hypoxia, and oxidative stress. Evidence supports that Interleukin-6 can shift MSH3 protein from its nuclear locale to the cytosol, allowing accumulation of mutations and double strand breaks. It is believed that these genetic changes modify the tumor behavior, as patients with EMAST cancers present with advanced stage and are more likely to have metastasis.

Mentions: Oxidative stress could be generated from a number of sources within a colorectal cancer. Tseng-Rogenski et al. examined pro-inflammatory cytokines as a potential source. After ruling out TNFα, IL1β, IFNα and IFNγ, the authors show that IL6 induces the MSH3 nuclear-to-cytosol compartmental shift, and is coincident with the generation of oxidative stress within colorectal cancer cells and non-transformed colon cells [31]. The MSH3 shift is dependent on IL6 trans-signaling through its soluble IL6 receptor and phosphorylation of STAT3 [31]. Mutations at genomic tetranucleotide loci were detected within two weeks in cells under IL6 treatment. Additionally, the authors show a strong correlation between IL6 presence in the colorectal cancer and EMAST [31]. These data indicate that the pro-inflammatory cytokine IL6 may be responsible for EMAST. The novel mechanism of mis-compartmentalization to inactivate MSH3 function in human cells is unique, and does not alter anything at the genetic or epigenetic level. In murine cells, MSH3 is a nuclear protein with a fine granular nucleoplasmic distribution and absent from condensed heterochromatin [36]. Upon ethanol or hydrogen peroxide treatment, murine MSH3 redistributed into nuclear bodies containing PCNA [36]. Overall, these observations further tie together previous findings of the convergence of inflammation, oxidative stress, MSH3 heterogeneous expression, and EMAST. With evidence that EMAST can worsen patient outcome from colorectal cancer, reducing the cause of EMAST appears to be a fruitful area in which may have a positive impact on patient care. Areas that might be targeted could be the inflammation itself, the IL6 signaling pathway, or the shuttling mechanism for MSH3, which at this time is not understood. One potential model for colorectal cancer based on the above information is presented in Figure 3.


EMAST is a Form of Microsatellite Instability That is Initiated by Inflammation and Modulates Colorectal Cancer Progression.

Carethers JM, Koi M, Tseng-Rogenski SS - Genes (Basel) (2015)

A model for modulation of the pathogenesis of colorectal cancer by EMAST. After the tumor has initiated, inflammation can modify the DNA repair function within the tumor through cytokine signaling, hypoxia, and oxidative stress. Evidence supports that Interleukin-6 can shift MSH3 protein from its nuclear locale to the cytosol, allowing accumulation of mutations and double strand breaks. It is believed that these genetic changes modify the tumor behavior, as patients with EMAST cancers present with advanced stage and are more likely to have metastasis.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4488660&req=5

genes-06-00185-f003: A model for modulation of the pathogenesis of colorectal cancer by EMAST. After the tumor has initiated, inflammation can modify the DNA repair function within the tumor through cytokine signaling, hypoxia, and oxidative stress. Evidence supports that Interleukin-6 can shift MSH3 protein from its nuclear locale to the cytosol, allowing accumulation of mutations and double strand breaks. It is believed that these genetic changes modify the tumor behavior, as patients with EMAST cancers present with advanced stage and are more likely to have metastasis.
Mentions: Oxidative stress could be generated from a number of sources within a colorectal cancer. Tseng-Rogenski et al. examined pro-inflammatory cytokines as a potential source. After ruling out TNFα, IL1β, IFNα and IFNγ, the authors show that IL6 induces the MSH3 nuclear-to-cytosol compartmental shift, and is coincident with the generation of oxidative stress within colorectal cancer cells and non-transformed colon cells [31]. The MSH3 shift is dependent on IL6 trans-signaling through its soluble IL6 receptor and phosphorylation of STAT3 [31]. Mutations at genomic tetranucleotide loci were detected within two weeks in cells under IL6 treatment. Additionally, the authors show a strong correlation between IL6 presence in the colorectal cancer and EMAST [31]. These data indicate that the pro-inflammatory cytokine IL6 may be responsible for EMAST. The novel mechanism of mis-compartmentalization to inactivate MSH3 function in human cells is unique, and does not alter anything at the genetic or epigenetic level. In murine cells, MSH3 is a nuclear protein with a fine granular nucleoplasmic distribution and absent from condensed heterochromatin [36]. Upon ethanol or hydrogen peroxide treatment, murine MSH3 redistributed into nuclear bodies containing PCNA [36]. Overall, these observations further tie together previous findings of the convergence of inflammation, oxidative stress, MSH3 heterogeneous expression, and EMAST. With evidence that EMAST can worsen patient outcome from colorectal cancer, reducing the cause of EMAST appears to be a fruitful area in which may have a positive impact on patient care. Areas that might be targeted could be the inflammation itself, the IL6 signaling pathway, or the shuttling mechanism for MSH3, which at this time is not understood. One potential model for colorectal cancer based on the above information is presented in Figure 3.

Bottom Line: MSI-H is highly correlated with loss of MMR protein expression, is commonly diploid, is often located in the right side of the colon, prognosticates good patient outcome, and predicts poor efficacy with 5-fluorouracil treatment.Elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) is another form of MSI at tetranucleotide repeats that has been observed in multiple cancers, but its etiology and clinical relevance to patient care has only been recently illuminated.Tumor hypoxia may also be a contributor.

View Article: PubMed Central - PubMed

Affiliation: Division of Gastroenterology, Department of Internal Medicine, University of Michigan, 3101 Taubman Center, 1500 East Medical Center Drive, Ann Arbor, MI 48109, USA. jcarethe@umich.edu.

ABSTRACT
DNA mismatch repair (MMR) function is critical for correcting errors coincident with polymerase-driven DNA replication, and its proteins are frequent targets for inactivation (germline or somatic), generating a hypermutable tumor that drives cancer progression. The biomarker for defective DNA MMR is microsatellite instability-high (MSI-H), observed in ~15% of colorectal cancers, and defined by mono- and dinucleotide microsatellite frameshift mutations. MSI-H is highly correlated with loss of MMR protein expression, is commonly diploid, is often located in the right side of the colon, prognosticates good patient outcome, and predicts poor efficacy with 5-fluorouracil treatment. Elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) is another form of MSI at tetranucleotide repeats that has been observed in multiple cancers, but its etiology and clinical relevance to patient care has only been recently illuminated. Specifically, EMAST is an acquired somatic defect observed in up to 60% of colorectal cancers and caused by unique dysfunction of the DNA MMR protein MSH3 (and its DNA MMR complex MutSβ, a heterodimer of MSH2-MSH3), and in particular a loss-of-function phenotype due to a reversible shift from its normal nuclear location into the cytosol in response to oxidative stress and the pro-inflammatory cytokine interleukin-6. Tumor hypoxia may also be a contributor. Patients with EMAST colorectal cancers show diminished prognosis compared to patients without the presence of EMAST in their cancer. In addition to defective DNA MMR recognized by tetranucleotide (and di- and tri-nucleotide) frameshifts, loss of MSH3 also contributes to homologous recombination-mediated repair of DNA double stranded breaks, indicating the MSH3 dysfunction is a complex defect for cancer cells that generates not only EMAST but also may contribute to chromosomal instability and aneuploidy. Areas for future investigation for this most common DNA MMR defect among colorectal cancers include relationships between EMAST and chemotherapy response, patient outcome with aneuploid changes in colorectal cancers, target gene mutation analysis, and mechanisms related to inflammation-induced compartmentalization and inactivation for MSH3.

No MeSH data available.


Related in: MedlinePlus