Simultaneous progression of oxidative stress and angiogenesis in malignant transformation of Barrett esophagus.
BACKGROUND
Oxidative stress and angiogenesis are important elements in the pathogenesis of inflammatory diseases and cancer. Our aim was to evaluate the role of both and of antioxidant capacity in the metaplasia-dysplasia-adenocarcinoma sequence in Barrett epithelium.


METHODS
In mucosal specimens from 59 patients grouped as having symptomatic gastroesophageal reflux disease, Barrett epithelium, or adenocarcinoma in the esophagus, plus controls, we measured myeloperoxidase activity, superoxidase dismutase activity, glutathione content, and total aromatic DNA adducts. To evaluate blood vessel densities and angioarchitecture, we used immunohistochemistry and a modified whole-mount technique. Sections were stained with endothelium-specific markers and smooth muscle cell actin.


RESULTS
The reflux disease-metaplasia-carcinoma sequence revealed progressively increased oxidative stress (increased myeloperoxidase activity), decreased antioxidant capacity (glutathione content), and simultaneous formation of DNA adducts. Pooled data show a negative correlation between glutathione content and DNA adducts (-0.28; P =.05). This sequence was also characterized by increased intensity in microvessels and an increasing percentage of immature blood vessels. In addition, the whole-mount technique offered 3-dimensional evidence that the rich new vascular bed is highly abnormal, with repeated twists, bends, or turns, even in nonmalignant Barrett esophagus.


CONCLUSIONS
Increased oxidative stress, decreased antioxidant capacity, and a negative correlation between glutathione content and DNA adduct formation indicate a link between oxidative stress and malignant transformation of Barrett epithelium. Simultaneously, this transformation acquires angiogenic capacity, strong neovascularization, and abnormal angioarchitecture.
Sihvo
Eero I T
EI
Department of Surgery, Helsinki University Central Hospital, Finland.
Ruohtula
Terhi
T
Auvinen
Merja I
MI
Koivistoinen
Aki
A
Harjula
Ari L
AL
Salo
Jarmo A
JA
D000230:Adenocarcinoma / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D000328:Adult; D000368:Aged; D001471:Barrett Esophagus / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D002471:Cell Transformation, Neoplastic; D018736:DNA Adducts / Q000032:analysis; D004938:Esophageal Neoplasms / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D004947:Esophagus / Q000098:blood supply / Q000378:metabolism; D005764:Gastroesophageal Reflux / Q000150:complications; D005978:Glutathione / Q000032:analysis; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D009092:Mucous Membrane / Q000098:blood supply / Q000378:metabolism; D009389:Neovascularization, Pathologic; D018384:Oxidative Stress; D009195:Peroxidase / Q000032:analysis; D013482:Superoxide Dismutase / Q000032:analysis
D018736:DNA Adducts; D009195:Peroxidase; D013482:Superoxide Dismutase; D005978:Glutathione