Field defects in progression to adenocarcinoma of the colon and esophagus

Bernstein, Carol; Bernstein, Harris; Payne, Claire M.; Garewal, Harinder S.

doi:10.2225/vol3-issue3-fulltext-1

Cited by 6 publications

(5 citation statements)

References 64 publications

(76 reference statements)

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“…A "field defect" or "field of cancerization" is a region of tissue that precedes and predisposes to the development of cancer [1]. As we show here, field defects have been identified in most of the major areas subject to tumorigenesis in the gastrointestinal tract.…”

Section: Introductionmentioning

confidence: 61%

Field defects in progression to gastrointestinal tract cancers

Bernstein

Payne

et al. 2008

Cancer Letters

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A field of defective tissue may represent a pre-malignant stage in progression to many cancers. However, field defects are often overlooked in studies of cancer progression through assuming tissue at some distance from the cancer is normal. We indicate, however, the generality of field defects in gastrointestinal cancers, including cancers of the oropharynx, esophagus, stomach, bile duct, pancreas, small intestine and colon/rectum. Common features of these field defects are reduced apoptosis competence, aberrant proliferation and genomic instability. These features are often associated with high bile acid exposure and may explain the association of dietary-related factors with cancer progression.

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Section: Introductionmentioning

confidence: 61%

Field defects in progression to gastrointestinal tract cancers

Bernstein

Payne

et al. 2008

Cancer Letters

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“…2B). Two patients (patients 3 and 9) also exhibited an increase in IL-6 secreted from squamous epithelium adjacent to BE, indicating a possible field defect (9).…”

Section: Resultsmentioning

confidence: 96%

Increased Expression and Secretion of Interleukin-6 in Patients with Barrett’s Esophagus

Dvořáková

Payne

Ramsey³

et al. 2004

Clinical Cancer Research

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Purpose: Barrett's esophagus (BE) is a common premalignant lesion of the distal part of the esophagus that arises as a consequence of chronic duodenogastroesophageal reflux. Interleukin (IL)-6 is a pleiotropic cytokine that regulates immune defense mechanisms and hematopoiesis. In addition, IL-6 may also be involved in malignant transformation and tumor progression. IL-6 has been shown to inhibit apoptosis. The major aim of this study was to evaluate expression of IL-6 in BE at the protein and mRNA levels. In addition, we tested whether proteins that are associated with IL-6 signaling, phosphorylated signal transducer and activator of transcription 3 and two antiapoptotic proteins, Bcl-x L and Mcl-1, are also expressed in the same tissues.Experimental Design: Biopsies of duodenum, BE, and squamous epithelium were evaluated by using a human cytokine protein array, ELISA, real-time PCR, and immunohistochemistry.Results: Increased IL-6 levels were found to be secreted from BE tissue compared with duodenum or squamous epithelium from sites adjacent or 5 cm away from the BE lesion. IL-6 mRNA was also elevated in BE compared with duodenum or squamous epithelium in five of seven patients.Immunohistochemical studies confirmed IL-6 expression in intestinal glandular epithelium in BE tissue. Activated signal transducer and activator of transcription 3, Mcl-1, and Bcl-x L are present at higher levels in BE glands, with lower levels being found in duodenum or squamous epithelium Conclusions: These data, taken together, suggest that elevated IL-6 levels in BE may contribute to the development of apoptosis resistance, thereby placing this epithelium at higher risk of developing malignancy.

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“…BE appears to result from chronic, repeated irritation of the esophageal mucosa by gastric acids, proteases, and bile acids that lasts several years (8,44). Several different theories exist on the cell of BE origin (57).…”

Section: Discussionmentioning

confidence: 99%

Characterization of squamous esophageal cells resistant to bile acids at acidic pH: implication for Barrett's esophagus pathogenesis

Goldman

Chen²,

Roesly³

et al. 2011

American Journal of Physiology-Gastrointestinal and Liver Physi

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Barrett's esophagus (BE) is a premalignant condition, where normal squamous epithelium is replaced by intestinal epithelium. BE is associated with an increased risk of developing esophageal adenocarcinoma (EAC). However, the BE cell of origin is not clear. We hypothesize that BE tissue originates from esophageal squamous cells, which can differentiate to columnar cells as a result of repeated exposure to gastric acid and bile acids, two components of refluxate implicated in BE pathology. To test this hypothesis, we repeatedly exposed squamous esophageal HET1A cells to 0.2 mM bile acid (BA) cocktail at pH 5.5 and developed an HET1AR-resistant cell line. These cells are able to survive and proliferate after repeated 2-h treatments with BA at pH 5.5. HET1AR cells are resistant to acidification and express markers of columnar differentiation, villin, CDX2, and cytokeratin 8/18. HET1AR cells have increased amounts of reactive oxygen species, concomitant with a decreased level and activity of manganese superoxide dismutase compared with parental cells. Furthermore, HET1AR cells express proteins and activate signaling pathways associated with inflammation, cell survival, and tumorigenesis that are thought to contribute to BE and EAC development. These include STAT3, NF-κB, epidermal growth factor receptor (EGFR), cyclooxygenase-2, interleukin-6, phosphorylated mammalian target of rapamycin (p-mTOR), and Mcl-1. The expression of prosurvival and inflammatory proteins and resistance to cell death could be partially modified by inhibition of STAT3 signaling. In summary, our study shows that long-term exposure of squamous cells to BA at acidic pH causes the cells to display the same characteristics and markers as BE.

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Field defects in progression to adenocarcinoma of the colon and esophagus

Cited by 6 publications

References 64 publications

Field defects in progression to gastrointestinal tract cancers

Field defects in progression to gastrointestinal tract cancers

Increased Expression and Secretion of Interleukin-6 in Patients with Barrett’s Esophagus

Characterization of squamous esophageal cells resistant to bile acids at acidic pH: implication for Barrett's esophagus pathogenesis

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