Incipient angiogenesis in Barrett's epithelium and lymphangiogenesis in Barrett's adenocarcinoma.

PURPOSE: Barrett's esophagus (BE), a precancerous condition for Barrett's adenocarcinoma, is classically characterized by flames of salmon-colored mucosa extending into normal pale esophageal mucosa. This flaming is thought to be a consequence of continuous erosis of mucosa caused by chronic reflux. Another characteristic feature of Barrett's adenocarcinoma patients is the frequent development of lymph node metastases. We addressed whether onset of angiogenesis occurs in BE and if the lymphatic system might provide a route for Barrett's adenocarcinoma cells to infiltrate regular lymph nodes. PATIENTS AND METHODS: Fifteen surgically resected Barrett's dysplasia or adenocarcinoma patients were included. Immunohistochemistry and a modified whole mount analysis were used. RESULTS: The incipient angiogenesis originates from the pre-existing vascular network in the lamina propria and infiltrates Barrett's epithelium, giving its ominous salmon-red color. Barrett's epithelium-specific goblet cells express vascular endothelial growth factor (VEGF)-A. The immature blood vessels show a relative absence of smooth muscle actin (SMA)-positive mural cells and express VEGF receptor (VEGFR)-2 and matrix metalloproteinase (MMP)-9 on their exterior. Coexpression of VEGF-C and its receptor VEGFR-3 on lymphatic vessels is demonstrated. CONCLUSION: BE is strongly neovascularized not eroded. This novel concept of a molecular mechanism of the origin of BE might emphasize why precancerous BE can give rise to the more cancerous dysplasia and Barrett's adenocarcinoma stages. In addition, adenocarcinoma cells induce lymphangiogenesis. The new lymphangiogenic vessels might provide a systemic route for adenocarcinoma cells to invade circulation and induce lymph node metastasis.

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.

Oxidative stress has a role in malignant transformation in Barrett's oesophagus.

Mechanisms underlying the development of oesophageal adenocarcinoma are poorly understood. To discover the role of oxidative stress and radical scavenger capacity in the malignant transformation of Barrett's oesophagus, we measured myeloperoxidase activity, superoxide dismutase activity, glutathione content and total aromatic DNA adducts. Mucosal specimens came from 52 patients in 6 groups: symptomatic gastro-oesophageal reflux disease (GORD) without and with endoscopic oesophagitis, Barrett's epithelium without and with dysplasia, adenocarcinoma in the oesophagus and controls. In the GORD-oesophagitis-metaplasia-dysplasia-adenocarcinoma sequence, glutathione content was progressively lower and myeloperoxidase activity higher than in controls, plateauing at Barrett's epithelium without dysplasia. Only in Barrett's epithelium with dysplasia was SOD activity significantly increased. In all patient groups, DNA adduct levels were significantly higher than the control level. Though these levels between patient groups did not differ significantly, the level was highest in Barrett's epithelium without dysplasia and progressively lower in Barrett's with dysplasia and adenocarcinoma. Pooled data showed a negative correlation between glutathione content and DNA adducts (-0.28, p = 0.05). Simultaneous formation of DNA adducts, increased myeloperoxidase-related oxidative stress, decreased antioxidant capacity (glutathione content) and the negative correlation between glutathione content and DNA adducts in the GORD-oesophagitis-metaplasia-dysplasia-adenocarcinoma sequence of Barrett's oesophagus indicate a role in the pathogenesis and malignant transformation related to oxidative stress.