The ‘angiogenic switch’ in the progression from Barrett's metaplasia to esophageal adenocarcinoma

Möbius, Christian; Stein, Hubert J.; Becker, Ingrid; Feith, Marcus; Theisen, Jörg; Gais, Peter; Jütting, Uta; Siewert, J. R.

doi:10.1016/j.ejso.2003.07.002

Cited by 52 publications

(40 citation statements)

References 18 publications

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“…[1][2][3][4][5][6]14,15 Although previous studies established a trend in the metaplasia-dysplasia-carcinoma sequence, none have clearly demonstrated whether high-grade dysplasia is significantly different from metaplasia or lowgrade dysplasia. Our study specifically demonstrates a significant and stepwise increase in microvascular density between Barrett' esophagus, low-grade dysplasia and high-grade dysplasia, which has not been previously shown.…”

Section: Discussionmentioning

confidence: 99%

“…Intestinal metaplasia and dysplasia have been studied in terms of microvascular density, and neoangiogenesis is thought to begin in these precursor lesions. [3][4][5][6][7] …”

mentioning

confidence: 99%

“…Intestinal metaplasia and dysplasia have been studied in terms of microvascular density, and neoangiogenesis is thought to begin in these precursor lesions. [3][4][5][6][7] Endoscopists are exploiting neovascularization in Barrett's esophagus to detect neoplasia using novel imaging modalities, such as narrow band imaging and confocal laser endomicroscopy. [8][9][10][11][12] One of the features that endoscopists look for is the vascular pattern under narrow band imaging or confocal laser endomicroscopy.…”

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confidence: 99%

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Evaluation of microvascular density in Barrett's associated neoplasia

et al. 2013

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Angiogenesis has an important role in the carcinogenesis of esophageal adenocarcinoma, however, the diagnostic and prognostic utility of microvascular density counts have not been clinically established. The aim of this study is to assess the correlation between microvascular density and disease progression of non-dysplastic Barrett's esophagus, low-grade dysplasia, high-grade dysplasia and invasive carcinoma in the superficial aspects of the tissue. Archival histological specimens from two referral centers for Barrett's esophagus and esophageal cancer were selected for review. A total of 160 regions marked according to histological grade were assessed with digitally interactive software to measure microvascular density. This was quantified in three levels: 0-50, 50-100 and 100-150 lm. In the areas of gastric cardia, Barrett's esophagus, low-grade dysplasia, high-grade dysplasia and cancer, microvascular density was significantly different (Po0.0001) among the five groups in the most superficial 150 lm of the mucosa. Furthermore, when examining the pairwise difference between the groups, there was a significant difference between cancer and each of the lower grades of histology (Po0.05) and between high-grade dysplasia and each of the lower grades of histology (Po0.05). These statistically significant differences were preserved in examining the depth at the most superficial 50 lm. We have used digital pathology to demonstrate a significant and stepwise increase in microvascular density, which supports the hypothesis that angiogenesis has a key role in Barrett's carcinogenesis. Furthermore, the differences in the most superficial mucosal layers are consistent with findings of increased vascularity by depth-restricted imaging modalities. Modern Pathology (2013) 26, 125-130; doi:10.1038/modpathol.2012 published online 24 August 2012 Keywords: angiogenesis; Barrett's esophagus; esophageal cancer; microvascular density Angiogenesis has an important role in the carcinogenesis of esophageal adenocarcinoma, however, the diagnostic and prognostic utility of microvascular density counts have not been clinically established. 1,2 Esophageal adenocarcinoma arises from Barrett's esophagus in a metaplasia-dysplasia-carcinoma sequence. Intestinal metaplasia and dysplasia have been studied in terms of microvascular density, and neoangiogenesis is thought to begin in these precursor lesions. [3][4][5][6][7]

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Section: Discussionmentioning

confidence: 99%

“…Intestinal metaplasia and dysplasia have been studied in terms of microvascular density, and neoangiogenesis is thought to begin in these precursor lesions. [3][4][5][6][7] …”

mentioning

confidence: 99%

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confidence: 99%

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Evaluation of microvascular density in Barrett's associated neoplasia

et al. 2013

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“…28 Immunohistochemical analysis of angiogenic regulators in human breast pathologies highlights the complexity of angiogenic regulation with progression. 29 While there are large numbers of data published in model systems touting novel regulators of an 'angiogenic switch', for example, [30][31][32][33] it seems far more likely that in human disease there are complex opposing systems that gradually lead to an increased angiogenic phenotype as a function of epithelial progression and stromal response. We have shown this for breast cancer, 3 others have shown this for colon cancer.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of VEGFR2 prevents DMBA-induced mammary tumor formation

Heffelfinger

Yan

Gear

et al. 2004

Laboratory Investigation

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Preinvasive mammary pathologies in humans and rat chemical carcinogenesis model systems have an increased microvascular density relative to normal tissue. This suggests the possibility of preventing invasive breast cancer by inhibiting angiogenesis. Vascular endothelial cell growth factor (VEGF) is a potent angiogenic growth factor, commonly involved in tumor-induced angiogenesis. Here, we show that both VEGF and VEGFR2 expression increase with histological progression to invasive disease in the rat 7,12-dimethylbenz [a]anthracene (DMBA) model. Other VEGF receptors, VEGFR1, neuropilin 1 and neuropilin 2, are constitutively expressed throughout progression. To examine whether VEGF signaling is functionally relevant to tumor-induced endothelial tubule formation in vitro and for tumor formation in vivo, we utilized the VEGFR2 inhibitor, ZD6474. In vitro endothelial cell tubulogenesis induced by isolated mammary organoids or carcinoma in situ from DMBA-treated rats is inhibited by ZD6474, in a dose-dependent fashion. The administration of ZD6474 to DMBAtreated rats inhibits the formation of atypical ductal hyperplasia and carcinoma in situ by greater than 95% (Po0.05), when administered 1 week or 6 weeks post-DMBA initiation. Invasive disease was absent in all ZD6474 cohorts. These data support the hypothesis that progression of DMBA-induced preinvasive mammary pathologies to palpable disease requires angiogenesis via a VEGF-dependent mechanism. Keywords: ZD6474; VEGF; VEGFR2; DMBA; chemoprevention Angiogenesis is the process of forming new vessels from pre-existing vessels, 1 and has been shown to be important in the process of breast cancer progression and metastasis. 2 We and others have shown that angiogenesis is also important in the process of breast cancer formation, as indicated by the stepwise increase in microvascular density with progression from normal epithelium to invasive disease. [3][4][5][6] In addition, we have shown that in the rat model system of DMBA-induced mammary tumor formation there is a similar pattern of upregulated microvascular density with progression. 7 Finally, if one isolates normal epithelium or tumor tissue from DMBA-treated rats, both are capable of inducing endothelial tubule formation in vitro, indicating that the angiogenic potential of these tissues is greater than that from vehicle-treated control rats. 7

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“…Studies have shown progressively increased HIF-1a expression in breast (Bos et al, 2001), skin (Costa et al, 2001), gastric (Griffiths et al, 2007) and cervical (Acs et al, 2003) cancer development. Hypoxia-inducible factor-1a is a key mediator of angiogenesis via activation of vascular endothelial growth factor (VEGF) (Forsythe et al, 1996), which is associated with oesophageal carcinogenesis (Couvelard et al, 2000;Auvinen et al, 2002;Lord et al, 2003;Mobius et al, 2003). Hypoxia-inducible erythropoietin (Epo) regulates erythropoiesis by stimulating the growth and differentiation of red blood cell precursors (Yasuda et al, 2003).…”

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Increasing expression of hypoxia-inducible proteins in the Barrett's metaplasia–dysplasia–adenocarcinoma sequence

Griffiths

Pritchard²,

McGrath³

et al. 2007

Br J Cancer

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Hypoxia-associated markers are involved in the progression of several malignancies, but are relatively unstudied in Barrett's carcinogenesis. Our aim was to assess the immunohistochemical expression of hypoxia-inducible factor (HIF)-1a, HIF-2a, erythropoietin (Epo), Epo receptor (Epo-R), Glut-1 and vascular endothelial growth factor (VEGF) along with Ki67/MIB-1 in the Barrett's metaplasia -dysplasia -adenocarcinoma sequence. Endoscopic biopsies of normal squamous epithelium (NSE) (n ¼ 20), columnar-lined oesophagus (CLO) (n ¼ 15), CLO with intestinal metaplasia (n ¼ 20), dysplasia (n ¼ 17) and Barrett's type adenocarcinoma (n ¼ 20) were obtained. Immunohistochemistry was performed on the paraffin-embedded tissue. A score was calculated for each marker (range 0À300) by multiplying intensity (none 0, weak 1, moderate 2, strong 3) by percentage of expression (range 0 -100). Significant increases in the expression of HIF-2a (P ¼ 0.014), VEGF (Po0.0001), Epo-R (Po0.0001) and Ki67 (Po0.0001) were found as tissue progressed from NSE to adenocarcinoma. HIF-2a was expressed late in the sequence and was only seen in dysplasia and adenocarcinoma. High HIF-2a expression was seen in 12 out of 20 Barrett's type adenocarcinoma. The late expression of HIF-2a in the Barrett's carcinogenesis sequence and its high expression in adenocarcinoma suggest that it is worth further investigation as a marker of disease progression and therapeutic target.

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The ‘angiogenic switch’ in the progression from Barrett's metaplasia to esophageal adenocarcinoma

Cited by 52 publications

References 18 publications

Evaluation of microvascular density in Barrett's associated neoplasia

Evaluation of microvascular density in Barrett's associated neoplasia

Inhibition of VEGFR2 prevents DMBA-induced mammary tumor formation

Increasing expression of hypoxia-inducible proteins in the Barrett's metaplasia–dysplasia–adenocarcinoma sequence

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